CDK-inhibitory pyrimidines, their production and use as pharmaceutical agents

ABSTRACT

This invention relates to pyrimidine derivatives of general formula I 
                         
in which R 1 , R 2 , X, A and B have the meanings that are contained in the description, as inhibitors of the cyclin-dependent kinases, their production as well as their use as medications for treating various diseases.

This application is a divisional of U.S. patent application Ser. No. 10/156,759, filed Nov. 7, 2002.

This invention relates to pyrimidine derivatives, their production as well as their use as medications for treating various diseases.

The CDKs (cyclin-dependent kinase) is an enzyme family that plays an important role in the regulation of the cell cycle and thus is an especially advantageous target for the development of small inhibitory molecules. Selective inhibitors of the CDKs can be used for treating cancer or other diseases that cause disruptions of cell proliferation.

Pyrimidines and analogs are already described as active ingredients, such as, for example, the 2-anilino-pyrimidines as fungicides (DE 4029650) or substituted pyrimidine derivatives for treating neurological or neurodegenerative diseases (WO 99/19305). As CDK inhibitors, the most varied pyrimidine derivatives are described, for example bis(anilino)-pyrimidine derivatives (WO 00/12486), 2-amino-4-substituted pyrimidines (WO 01/14375), purines (WO 99/02162), 5-cyano-pyrimidines (WO 02/04429), anilinopyrimidines (WO 00/12486) and 2-hydroxy-3-N,N-dimethylaminopropoxy-pyrimidines (WO 00/39101).

The object of this invention is to provide compounds that have better properties than the inhibitors that are already known. The substances that are described here are more effective, since they already inhibit in the nanomolar range and can be distinguished from other already known CDK inhibitors such as, e.g., olomoucine and roscovitine.

It has now been found that compounds of general formula I

in which

-   -   R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, nitro, or for the         group —COR⁵, —OCF₃, —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃,     -   R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or         C₃-C₁₀-cycloalkyl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,         C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl that is substituted in one         or more places in the same way or differently with hydroxy,         halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano,         C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl,         C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,         C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,         —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl),         —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵,         C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,         —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂         or with the group —R⁶ or —NR³R⁴, and the phenyl,         C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and         —(CH₂)_(n)-heteroaryl itself optionally can be substituted in         one or more places in the same way or differently with halogen,         hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, heteroaryl, benzoxy or with         the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl         and the C₁-C₁₀-alkyl optionally can be interrupted by one or         more nitrogen, oxygen and/or sulfur atoms and/or can be         interrupted by one or more ═C═O groups in the ring and/or         optionally one or more possible double bonds can be contained in         the ring, or     -   R² stands for the group

-   -   X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or         for —OC₃-C₁₀-cycloalkyl, which can be substituted in one or more         places in the same way or differently with a heteroaromatic         compound,         -   or     -   X and R² together form a C₃-C₁₀-cycloalkyl ring, which         optionally can contain one or more heteroatoms and optionally         can be substituted in one or more places with hydroxy,         C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen,     -   A and B, in each case independently of one another, stand for         hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group         —SR⁷, —S(O)R⁷, —SO₂R⁷, —NHSO₂R⁷, —CH(OH)R⁷, —CR⁷(OH)—R⁷,

C₁-C₆-alkylP(O)OR³OR⁴ or —COR⁷, or for

-   -   -   or

    -   A and B together form a C₃-C₁₀-cycloalkyl ring that optionally         can be interrupted by one or more nitrogen, oxygen and/or sulfur         atoms and/or can be interrupted by one or more ═C═O or ═SO₂         groups in the ring and/or optionally one or more possible double         bonds can be contained in the ring, and the C₃-C₁-cycloalkyl         ring optionally can be substituted in one or more places in the         same way or differently with hydroxy, halogen, C₁-C₆-alkoxy,         C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, C₂-C₆-alkenyl,         C₃-C₁₀-cycloalkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl,         —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂R⁷, C₁-C₆-alkanoyl,         —CONR³R⁴, —COR⁵, C₁-C₆-alkoxyOAc, phenyl or with the group R⁶,         whereby the phenyl itself optionally can be substituted in one         or more places in the same way or differently with halogen,         hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃ or         —OCF₃,

    -   R³ and R⁴, in each case independently of one another, stand for         hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy,         C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy,         hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, heteroaryl,         heterocyclo-C₃-C₁₀-alkyl, heteroaryl-C₁-C₃-alkyl,         C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with         cyano, or for C₁-C₆-alkyl that is optionally substituted in one         or more places in the same way or differently with phenyl,         pyridyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or         C₁-C₆-alkoxy,         -   whereby the phenyl itself can be substituted in one or more             places in the same way or differently with halogen,             C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴,         -   or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴,         -   or

    -   R³ and R⁴ together form a C₃-C₁₀-cycloalkyl ring that optionally         can be interrupted by one or more nitrogen, oxygen and/or sulfur         atoms and/or can be interrupted by one or more ═C═O groups in         the ring and/or optionally one or more possible double bonds can         be contained in the ring,

    -   R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,         benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy,

    -   R⁶ stands for a heteroaryl or C₃-C₁₀-cycloalkyl ring, whereby         the ring has the above-indicated meaning,

    -   R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl,         C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₁₀-cycloalkyl, with the         above-indicated meaning, or for the group —NR³R⁴, or for         C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl or C₃-C₇-cycloalkyl         that is substituted in one or more places in the same way or         differently with hydroxy, C₁-C₆-alkoxy, halogen, phenyl, —NR³R⁴         or phenyl, which itself can be substituted in one or more places         in the same way or differently with halogen, hydroxy,         C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, or         halo-C₁-C₆-alkoxy, or R⁷ stands for phenyl, which itself can be         substituted in one or more places in the same way or differently         with halogen, hydroxy, C₁-C₆-alkyl or C₁-C₆-alkoxy,         halo-C₁-C₆-alkyl, or halo-C₁-C₆-alkoxy,

    -   R⁸, R⁹ and

    -   R¹⁰, in each case independently of one another, stand for         hydrogen, hydroxy, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl,         C₃-C₁₀-cycloalkyl, aryl, or heteroaryl or for C₁-C₁₀-alkyl,         C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl or C₃-C₁₀-cycloalkyl that is         substituted in one or more places in the same way or differently         with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino,         cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl,         C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,         C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,         C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl,         —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl),         C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl,         heteroaryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl,         phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or         —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, heteroaryl,         —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl itself optionally can         be substituted in one or more places in the same way or         differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or         with the group —CF₃ or —OCF₃, and the ring of C₃-C₁₀-cycloalkyl         and the C₁-C₁₀-alkyl optionally can be interrupted by one or         more nitrogen, oxygen and/or sulfur atoms and/or can be         interrupted by one or more ═C═O groups in the ring and/or         optionally one or more possible double bonds can be contained in         the ring, and

    -   n stands for 0-6,         as well as isomers, diastereomers, enantiomers and salts thereof         that overcome known drawbacks.

Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.

Alkoxy is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, isopentyloxy, or hexyloxy.

Alkylthio is defined in each case as a straight-chain or branched alkylthio radical, such as, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio or hexylthio.

Cycloalkyl is defined in general as monocyclic alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, but also bicyclic rings or tricyclic rings such as, for example, norbornyl, adamantanyl, etc.

The ring systems, in which optionally one or more possible double bonds can be contained in the ring, are defined as, for example, cycloalkenyls, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl, whereby the linkage can be carried out both to the double bond and to the single bonds.

If A and B, R³ and R⁴, X and R², in each case independently of one another, together form a C₃-C₁₀-cycloalkyl ring, which optionally can be interrupted by one or more heteroatoms, such as nitrogen atoms, oxygen atoms and/or sulfur atoms, and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, the above-mentioned definitions, however, are also intended to include heteroaryl radical or heterocycloalkyl and heterocycloalkenyl.

Halogen is defined in each case as fluorine, chlorine, bromine or iodine.

The alkenyl substitutents in each case are straight-chain or branched, whereby, for example, the following radicals are meant: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, ethinyl, prop-1-in-1-yl, but-1-in-1-yl, but-2-in-1-yl, but-3-en-1-yl, and allyl.

Alkinyl is defined in each case as a straight-chain or branched alkinyl radical that contains 2-6, preferably 2-4, C atoms. For example, the following radicals can be mentioned: acetylene, propin-1-yl, propin-3-yl, but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.

The aryl radical in each case comprises 3-12 carbon atoms and in each case can be benzocondensed.

For example, there can be mentioned: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, etc.

The heteroaryl radical in each case comprises 3-16 ring atoms, and instead of the carbon can contain one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, in the ring, and can be monocyclic, bicyclic, or tricyclic and in addition in each case can be benzocondensed.

For example, there can be mentioned:

Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, e.g., quinolyl, isoquinolyl, etc., or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl, etc.

Heterocycloalkyl stands for an alkyl ring that comprises 3-12 carbon atoms, which instead of the carbon contains one or more heteroatoms that are the same or different, such as, e.g., oxygen, sulfur or nitrogen.

As heterocycloalkyls, there can be mentioned, e.g.: oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, etc.

Heterocycloalkenyl stands for an alkyl ring that comprises 3-12 carbon atoms, which instead of the carbon contains one or more heteroatoms that are the same or different, such as, e.g., oxygen, sulfur or nitrogen, and which is partially saturated.

As heterocycloalkenyls, there can be mentioned, e.g.: pyran, thiin, dihydroacet, etc.

If an acid group is included, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali and alkaline-earth salts, as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropane diol, Sovak base, and 1-amino-2,3,4-butanetriol.

If a basic group is included, the physiologically compatible salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, i.a.

Those compounds of general formula (I) in which

-   -   R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, nitro, or for the         group —COR⁵, —OCF₃, —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃,     -   R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or         C₃-C₁₀-cycloalkyl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,         C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl that is substituted in one         or more places in the same way or differently with hydroxy,         halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano,         C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl,         C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,         C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,         —NHC 16-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂         (C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc,         carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,         —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(5)₂ or         with the group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl,         aryl, heteroaryl, —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl         itself optionally can be substituted in one or more places in         the same way or differently with halogen, hydroxy, C₁-C₆-alkyl,         C₁-C₆ alkoxy, heteroaryl, benzoxy or with the group —CF₃ or         —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl and the         C₁-C₁₀-alkyl optionally can be interrupted by one or more         nitrogen, oxygen and/or sulfur atoms and/or can be interrupted         by one or more ═C═O groups in the ring and/or optionally one or         more possible double bonds can be contained in the ring, or     -   R² stands for the group

-   -   X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or         for —OC₃-C₁₀-cycloalkyl, which can be substituted in one or more         places in the same way or differently with a heteroaromatic         compound,         -   or     -   X and R together form a C₃-C₁₀-cycloalkyl ring, which optionally         can contain one or more heteroatoms and optionally can be         substituted in one or more places with hydroxy, C₁-C₆-alkyl,         C₁-C₆-alkoxy or halogen,     -   A and B, in each case independently of one another, stand for         hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group         —S—CH₃, —SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂,         —S—(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —CH₂P(O)OR³OR⁴, —S—CF₃, —SO—CH₃,         —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴, —SO₂—NR³R⁴, —SO₂R⁷, —CH—(OH)—CH₃         or for

-   -   -   or

    -   A and B together can form a group

-   -   R³ and R⁴, in each case independently of one another, stand for         hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy,         C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy,         hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, heteroaryl,         heterocyclo-C₃-C₁₀-alkyl, heteroaryl-C₁-C₃-alkyl,         C₃-C₆-cycloalkyl-C₁-C₃-alkyl optionally substituted with cyano,         or for C₁-C₆-alkyl that is optionally substituted in one or more         places in the same way or differently with phenyl, pyridyl,         phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy,         -   whereby the phenyl itself can be substituted in one or more             places in the same way or differently with halogen,             trifluoromethyl, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group             —SO₂NR³R⁴,         -   or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴         -   or for

-   -   -   which optionally can be substituted with C₁-C₆-alkyl,

    -   R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,         benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy,

    -   R⁶ stands for the group

-   -   R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, —C₂H₄H,         —NR³R⁴, or the group

-   -   R⁸, R⁹ and     -   R¹⁰, in each case independently of one another, stand for         hydrogen, hydroxy, C₁-C₆-alkyl, C₃-C₆-cycloalkyl or for the         group

-   -   -   and

    -   n stands for 0-6,         as well as isomers, enantiomers, diastereomers, and salts         thereof, are especially effective.

Those compounds of general formula I in which

-   -   R¹ stands for hydrogen, halogen, C₁-C₃-alkyl, or for the group         —(CH₂)_(n)R⁵,     -   R² stands for —CH(CH₃)—(CH₂)_(n)—R⁵, —CH—(CH₂OH)₂, —(CH₂)_(n)R⁷,         —CH(C₃H₇)—(CH₂)_(n)—R⁵, —CH(C₂H₅)—(CH₂)_(n)—R⁵, —CH₂—CN,         —CH(CH₃)COCH₃, —CH(CH₃)—C(OH)(CH₃)₂, —CH(CH(OH)CH₃)OCH₃,         CH(C₂H₅)CO—R⁵, C₂-C₄-alkinyl, —(CH₂)_(n)—COR⁵,         —(CH₂)_(n)—CO—C₁-C₆-alkyl, —(CH₂)_(n)—C(OH)(CH₃)-phenyl,         —CH(CH₃)—C(CH₃)—R⁵, —CH(CH₃)—C(CH₃)(C₂H₅)—R⁵, —CH(OCH₃)—CH₂—R⁵,         —CH₂—CH(OH)—R⁵, —CH(OCH₃)—CHR⁵—CH₃, —CH(CH₃)—CH(OH)—CH₂—CH═CH₂,         —CH(C₂H₅)—CH(OH)—(CH₂)_(n)—CH₃, —CH(CH₃)—CH(OH)—(CH₂)_(n)—CH₃,         —CH(CH₃)—CH(OH)—CH(CH₃)₂, (CH₂OAC)₂, —(CH₂)_(n)—R⁶,         —(CH₂)_(n)—(CF₂)_(n)—CF₃, —CH(CH₂)_(n)—R⁵)₂, —CH(CH₃)—CO—NH₂,         —CH(CH₂OH)-phenyl, —CH(CH₂OH)—CH(OH)—(CH₂)_(n)R⁵,         —CH(CH₂OH)—CH(OH)-phenyl, —CH(CH₂OH)—C₂H₄—R⁵,         —(CH₂)_(n)—C≡C(CH₃)═CH—COR⁵, —CH(Ph)-(CH₂)_(n)—R⁵,         —(CH₂)_(n)—COR⁵, —(CH₂)_(n)PO₃(R⁵)₂, —(CH₂)_(n)—COR⁵,         —CH((CH₂)_(n)OR⁵)CO—R⁵, —(CH₂)_(n)CONHCH((CH₂)_(n)R⁵)₂,         —(CH₂)_(n)NH—COR⁵, —CH(CH₂)_(n)R⁵—(CH₂)_(n)C₃-C₁₀-cycloalkyl,         —(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl; C₁-C₆-alkyl,         C₃-C₁₀-cycloalkyl, —(CH₂)_(n)—O—(CH₂)_(n)—R⁵, —(CH₂)_(n)—NR³R⁴         that is optionally substituted in one or more places in the same         way or differently with hydroxy, C₁-C₆-alkyl or the group         —COONH(CH₂)_(n)CH₃ or —NR³R⁴,         —CH(C₃H₇)—(CH₂)_(n)—OC(O)—(CH₂)_(n)—CH₃, —(CH₂)_(n)—R⁵,         —C(CH₃)₂—(CH₂)_(n)—R⁵, —C(CH₂)_(n)(CH₃)—(CH₂)_(n)R⁵,         —C(CH₂)_(n)—(CH₂)_(n)R⁵, —CH(t-butyl)-(CH₂)_(n)—R⁵,         —CCH₃(C₃H₇)—(CH₂)_(n)R⁵, —CH(C₃H₇)—(CH₂)_(n)—R⁵, —CH(C₃H₇)—COR⁵,         —CH(C₃H₇)—(CH₂)_(n)—OC(O)—NH—Ph,

—CH((CH₂)_(n)(C₃H₇))—(CH₂)R⁵, —CH(C₃H₇)—(CH₂)_(n)—OC(O)—NH—Ph(OR⁵)₃, —NR³R⁴, —NH—(CH₂)_(n)—NR³R⁴, R—(CH₂)_(n)—C*H—CH(R⁵)—(CH₂)_(n)—R⁵, —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CO—R⁵, —OC(O)NH—C₁-C₆-alkyl or —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CH—((CH₂)_(n)R⁵)₂,

-   -   -   or for C₃-C₁₀-cycloalkyl, which is substituted with the             group

-   -   -   or for the group

-   -   X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or

-   -   -   or

    -   R² stands for the group

-   -   X and R² together form a group

-   -   A and B, in each case independently of one another, stand for         hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group         —S—CH₃, —SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂,         —S(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —CH₂PO(OC₂H₅)₂, —S—CF₃, —SO—CH₃,         —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴, —SO₂—NR³R⁴, —SO₂R⁷, —CH(OH)—CH₃,         —COOH, —CH((CH₂)_(n)R⁵)₂, —(CH₂)_(n)R⁵, —COO—C₁-C₆-alkyl,         —CONR³R⁴ or for

-   -   -   or

    -   A and B together can form a group

-   -   R¹ and R⁴, in each case independently of one another, stand for         hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy,         C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy,         hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, heteroaryl,         heterocyclo-C₃-C₁₀-alkyl, heteroaryl-C₁-C₃-alkyl,         C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with         cyano, or for C₁-C₆-alkyl that is optionally substituted in one         or more places in the same way or differently with phenyl,         pyridyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or         C₁-C₆-alkoxy, whereby the phenyl itself can be substituted in         one or more places in the same way or differently with halogen,         trifluoromethyl, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group         —SO₂NR³R⁴,         -   or for the group —(CH₂)_(n)NR³R³R⁴, —CNHNH₂ or —NR³R⁴ or for

-   -   -   which optionally can be substituted with C₁-C₆-alkyl,

    -   R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,         benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy,

    -   R⁶ stands for the group

-   -   R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl,         —(CH₂)_(n)OH, —NR³R⁴ or the group

-   -   R⁸, R⁹ and     -   R¹⁰ stand for hydrogen, hydroxy, C₁-C₆-alkyl or for the group         —(CH₂)_(n)—COOH, and     -   n stands for 0-6,         as well as isomers, diastereomers, enantiomers and salts         thereof, have proven quite especially effective.

The compounds according to the invention essentially inhibit cyclin-dependent kinases, upon which is based their action, for example, against cancer, such as solid tumors and leukemia; auto-immune diseases such as psoriasis, alopecia, and multiple sclerosis, chemotherapy-induced alopecia and mucositis; cardiovascular diseases such as stenoses, arterioscleroses and restenoses; infectious diseases, such as, e.g., by unicellular parasites, such as trypanosoma, toxoplasma or plasmodium, or produced by fungi; nephrological diseases, such as, e.g., glomerulonephritis, chronic neurodegenerative diseases, such as Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases, such as ischemias of the brain and neurotraumas; viral infections, such as, e.g., cytomegalic infections, herpes, Hepatitis B and C, and HIV diseases.

The eukaryotic cell division ensures the duplication of the genome and its distribution to the daughter cells by passing through a coordinated and regulated sequence of events. The cell cycle is divided into four successive phases: the G1 phase represents the time before the DNA replication, in which the cell grows and is sensitive to external stimuli. In the S phase, the cell replicates its DNA, and in the G2 phase, preparations are made for entry into mitosis. In mitosis (M phase), the replicated DNA separates, and cell division is completed.

The cyclin-dependent kinases (CDKs), a family of serine/threonine kinases, whose members require the binding of a cyclin (Cyc) as a regulatory subunit in order for them to activate, drive the cell through the cell cycle. Different CDK/Cyc pairs are active in the various phases of the cell cycle. CDK/Cyc pairs that are important to the basic function of the cell cycle are, for example, CDK4(6)/CycD, CDK2/CycE, CDK2/CycA, CDK1/CycA and CDK1/CycB. Some members of the CDK enzyme family have a regulatory function by influencing the activity of the above-mentioned cell cycle CDKs, while no specific function could be associated with other members of the CDK enzyme family. One of the latter, CDK5, is distinguished in that it has an atypical regulatory subunit (p35) that deviates from the cyclins, and its activity is highest in the brain.

The entry into the cell cycle and the passage through the “restriction points,” which marks the independence of a cell from further growth signals for the completion of the cell division that has begun, are controlled by the activity of the CDK4(6)/CycD and CDK2/CycE complexes. The essential substrate of these CDK complexes is the retinoblastoma protein (Rb), the product of the retinoblastoma tumor suppressor gene. Rb is a transcriptional co-repressor protein. In addition to other, still largely little understood mechanisms, Rb binds and inactivates transcription factors of the E2F type and forms transcriptional repressor complexes with histone-deacetylases (HDAC) (Zhang, H. S. et al. (2000). Exit from G1 and S Phase of the Cell Cycle is Regulated by Repressor Complexes Containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell 101, 79-89). By the phosphorylation of Rb by CDKs, bonded E2F transcription factors are released and result in transcriptional activation of genes, whose products are required for the DNA synthesis and the progression through the S phase. In addition, the Rb-phosphorylation brings about the breakdown of the Rb-HDAC complexes, by which additional genes are activated. The phosphorylation of Rb by CDK's is to be treated as equivalent to exceeding the “restriction points.” For the progression through the S phase and its completion, the activity of the CDK2/CycE and CDK2/CycA complexes is necessary, e.g., the activity of the transcription factors of the E2F type is turned off by means of phosphorylation by CDK2/CycA as soon as the cells are entered into the S phase. After replication of DNA is complete, the CDK1 in the complex with CycA or CycB controls the entry into and the passage through phases G2 and M (FIG. 1).

According to the extraordinary importance of the cell-division cycle, the passage through the cycle is strictly regulated and controlled. The enzymes that are necessary for the progression through the cycle must be activated at the correct time and are also turned off again as soon as the corresponding phase is passed. Corresponding control points (“checkpoints”) stop the progression through the cell cycle if DNA damage is detected, or the DNA replication or the creation of the spindle device is not yet completed.

The activity of the CDKs is controlled directly by various mechanisms, such as synthesis and degradation of cyclins, complexing of the CDKs with the corresponding cyclins, phosphorylation and dephosphorylation of regulatory threonine and tyrosine radicals, and the binding of natural inhibitory proteins. While the amount of protein of the CDKs in a proliferating cell is relatively constant, the amount of the individual cyclins oscillates with the passage through the cycle. Thus, for example, the expression of CycD during the early G1 phase is stimulated by growth factors, and the expression of CycE is induced after the “restriction points” are exceeded by the activation of the transcription factors of the E2F type. The cyclins themselves are degraded by the ubiquitin-mediated proteolysis. Activating and inactivating phosphorylations regulate the activities of the CDKs, for example phosphorylate CDK-activating kinases (CAKs) Thr160/161 of the CDK1, while, by contrast, the families of Wee1/Myt1 inactivate kinases CDK1 by phosphorylation of Thr14 and Tyr15. These inactivating phosphorylations can be destroyed in turn by cdc25 phosphatases. The regulation of the activity of the CDK/Cyc complexes by two families of natural CDK inhibitor proteins (CKIs), the protein products of the p21 gene family (p21, p27, p57) and the p16 gene family (p15, p16, p18, p19) is very significant. Members of the p21 family bind to cyclin complexes of CDKs 1,2,4,6, but inhibit only the complexes that contain CDK1 or CDK2. Members of the p16 family are specific inhibitors of the CDK4 and CDK6 complexes.

The plane of control point regulation lies above this complex direct regulation of the activity of the CDKs. Control points allow the cell to track the orderly sequence of the individual phases during the cell cycle. The most important control points lie at the transition from G1 to S and from G2 to M. The G1 control point ensures that the cell does not initiate any DNA synthesis unless it has proper nutrition, interacts correctly with other cells or the substrate, and its DNA is intact. The G2/M control point ensures the complete replication of DNA and the creation of the mitotic spindle before the cell enters into mitosis. The G1 control point is activated by the gene product of the p53 tumor suppressor gene. p53 is activated after detection of changes in metabolism or the genomic integrity of the cell and can trigger either a stopping of the cell cycle progression or apoptosis. In this case, the transcriptional activation of the expression of the CDK inhibitor protein p21 by p53 plays a decisive role. A second branch of the G1 control point comprises the activation of the ATM and Chk1 kinases after DNA damage by UV light or ionizing radiation and finally the phosphorylation and the subsequent proteolytic degradation of the cdc25A phosphatase (Mailand, N. et al. (2000). Rapid Destruction of Human cdc25A in Response to DNA Damage. Science 288, 1425-1429). A shutdown of the cell cycle results from this, since the inhibitory phosphorylation of the CDKs is not removed. After the G2/M control point is activated by damage of the DNA, both mechanisms are involved in a similar way in stopping the progression through the cell cycle.

The loss of the regulation of the cell cycle and the loss of function of the control points are characteristics of tumor cells. The CDK-Rb signal path is affected by mutations in over 90% of human tumor cells. These mutations, which finally result in inactivating phosphorylation of the RB, include the over-expression of D- and E-cyclins by gene amplification or chromosomal translocations, inactivating mutations or deletions of CDK inhibitors of the p16 type, as well as increased (p27) or reduced (CycD) protein degradation. The second group of genes, which are affected by mutations in tumor cells, codes for components of the control points. Thus p53, which is essential for the G1 and G2/M control points, is the most frequently mutated gene in human tumors (about 50%).

In tumor cells that express p53 without mutation, it is often inactivated because of a greatly increased protein degradation. In a similar way, the genes of other proteins that are necessary for the function of the control points are affected by mutations, for example ATM (inactivating mutations) or cdc25 phosphatases (over-expression).

Convincing experimental data indicate that CDK2/Cyc complexes occupy a decisive position during the cell cycle progression: (1) Both dominant-negative forms of CDK2, such as the transcriptional repression of the CDK2 expression by anti-sense oligonucleotides, produce a stopping of the cell cycle progression. (2) The inactivation of the CycA gene in mice is lethal. (3) The disruption of the function of the CDK2/CycA complex in cells by means of cell-permeable peptides resulted in tumor cell-selective apoptosis (Chen, Y. N. P. et al. (1999). Selective Killing of Transformed Cells by Cyclin/Cyclin-Dependent Kinase 2 Antagonists. Proc. Natl. Acad. Sci. USA 96, 4325-4329).

Changes of the cell cycle control play a role not only in carcinoses. The cell cycle is activated by a number of viruses, both by transforming viruses as well as by non-transforming viruses, to make possible the replication of viruses in the host cell. The false entry into the cell cycle of normally post-mitotic cells is associated with various neurodegenerative diseases. The mechanisms of the cell cycle regulation, their changes in diseases and a number of approaches to develop inhibitors of the cell cycle progression and especially the CDKs were already described in a detailed summary in several publications (Sielecki, T. M. et al. (2000). Cyclin-Dependent Kinase Inhibitors: Useful Targets in Cell Cycle Regulation. J. Med. Chem. 43, 1-18; Fry, D. W. & Garrett, M. D. (2000). Inhibitors of Cyclin-Dependent Kinases as Therapeutic Agents for the Treatment of Cancer. Curr. Opin. Oncol. Endo. Metab. Invest. Drugs 2, 40-59; Rosiania, G. R. & Chang, Y. T. (2000). Targeting Hyperproliferative Disorders with Cyclin-Dependent Kinase Inhibitors. Exp. Opin. Ther. Patents 10, 215-230; Meijer, L. et al. (1999). Properties and Potential Applications of Chemical Inhibitors of Cyclin-Dependent Kinases. Pharmacol. Ther. 82, 279-284; Senderowicz, A. M. & Sausville, E. A. (2000). Preclinical and Clinical Development of Cyclin-Dependent Kinase Modulators. J. Natl. Cancer Inst. 92, 376-387).

To use the compounds according to the invention as pharmaceutical agents, the latter are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient for enteral or parenteral administration contains suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be present in solid form, for example as tablets, coated tablets, suppositories, or capsules, or in liquid form, for example as solutions, suspensions, or emulsions. Moreover, they optionally contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers; salts for changing the osmotic pressure or buffers. These pharmaceutical preparations are also subjects of this invention.

For parenteral administration, especially injection solutions or suspensions, especially aqueous solutions of active compounds in polyhydroxyethoxylated castor oil, are suitable.

As carrier systems, surface-active adjuvants such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof, as well as liposomes or their components can also be used.

For oral administration, especially tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as, for example, lactose, corn or potato starch, are suitable. The administration can also be carried out in liquid form, such as, for example, as a juice, to which optionally a sweetener is added.

Enteral, parenteral and oral administrations are also subjects of this invention.

The dosage of the active ingredients can vary depending on the method of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be given as a single dose to be administered once or divided into two or more daily doses.

Subjects of this invention also include the use of compounds of general formula I for the production of a pharmaceutical agent for treating cancer, auto-immune diseases, cardiovascular diseases, chemotherapy agent-induced alopecia and mucositis, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, whereby cancer is defined as solid tumors and leukemia; auto-immune diseases are defined as psoriasis, alopecia and multiple sclerosis; cardiovascular diseases are defined as stenoses, arterioscleroses and restenoses; infectious diseases are defined as diseases that are caused by unicellular parasites; nephrological diseases are defined as glomerulonephritis; chronic neurodegenerative diseases are defined as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases are defined as ischemias of the brain and neurotraumas; and viral infections are defined as cytomegalic infections, herpes, hepatitis B or C, and HIV diseases.

Subjects of this invention also include pharmaceutical agents for treating the above-cited diseases, which contain at least one compound according to general formula I, as well as pharmaceutical agents with suitable formulation substances and vehicles.

The compounds of general formula I according to the invention are, i.a., excellent inhibitors of the cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as the glycogen-synthase-kinase (GSK-3β).

If the production of the starting compounds is not described, these compounds are known or can be produced analogously to known compounds or to processes that are described here. It is also possible to perform all reactions that are described here in parallel reactors or by means of combinatory operating procedures.

The isomer mixtures can be separated into the enantiomers or E/Z isomers according to commonly used methods, such as, for example, crystallization, chromatography or salt formation.

The production of the salts is carried out in the usual way by a solution of the compound of formula I being mixed with the equivalent amount of or excess base or acid, which optionally is in solution, and the precipitate being separated or the solution being worked up in the usual way.

PRODUCTION OF THE COMPOUNDS ACCORDING TO THE INVENTION

The following examples explain the production of the compounds according to the invention, without the scope of the claimed compounds being limited to these examples.

The compounds of general formula I according to the invention can be produced according to the following general diagrams of the process:

EXAMPLE 1 Production of 5-Bromo-N2-(4-difluoromethylthiophenyl)-N4-2-propynyl-2,4-pyrimidine diamine (is Carried Out According to Process Diagram 1) (Compound 23)

245 mg (1 mmol) of 2-chloro-4-2-propynylaminopyrimidine is dissolved in 2 ml of acetonitrile, and a suspension of 4-(difluoromethylthio)-aniline hydrochloride [produced from 352 mg (2 mmol) of 4-(difluoromethylthio)-aniline, 1 ml of acetonitrile and 0.5 ml of aqueous HCl (4M in dioxane)] is added at room temperature. Then, the reaction mixture is refluxed overnight under N₂ atmosphere. After cooling, the mixture is filtered, the remaining solid phase is washed with H₂O and dried. A yield of 328 mg (85%) of the product can be expected

6H2CH 8.25(s, 1H)7.86(d, 2H)7.51(d, 2H)7.38(t, 56.8Hz, 1H) Yield:85%  Melting point:>235° C. 4C 4.18(m, 2H) H⁻ 3.16(sb, 1H) 10.24(sb, 1H) NH 8.17(sb, 1H)

EXAMPLE 2 Production of 5-bromo-N-(3-(oxiranylmethoxy)phenyl)-2-(2-propynyloxy)-2-pyrimidinamine (compound 51) is Carried Out According to Process Diagram 2

1.55 g (4.9 mmol) of compound 20 is dissolved in 5.5 ml of epibromohydrin, and 1.38 g of K₂CO₃ and 65 mg of tetrabutylammonium bromide are added to it. The reaction mixture is stirred under nitrogen atmosphere at 100° C. for 1 hour. After ethyl acetate is added, the resulting precipitate is collected and recrystallized from ethanol. The product yield is 1.15 g (62%) as a white powder.

6H2CH 8.45(s, 1H)7.47(s, 1H) 7.32(d, 1H) Yield: 62% 7.20(t, 1H) 6.40(d, 1H) Melting point: 173° C. 4.32(dd, 1H) 3.82(dd, 1H) 3.3-3.4 (m, 1H) 2.87(t, 1H) 2.72(dd, 1H) 4CH 5.13(d, 2H) 3.67(t, 1H) NH 9.84(sb, 1H)

Substance 40 is produced analogously to Example 2.

6-H2CH 8.36(s, 1H)7.60(d, 1H) Chromato-graphy:H/EA 1:30.5% TEA 6.91(d, 1H) 4.28(dd, 1H) 3.79(dd, 1H) Yield: 38% 3.31(m, 1H) 2.84(dd, 1H) Melting point: 2.70(dd, 1H) 140-141° C. 4CH 5.07(d, 12H) 3.65(t, 1H) NH 9.65(sb, 1H) OH

EXAMPLE 3 Production of 1-(4-((5-bromo-4-(2-propynyloxy)-pyrimidin-2-yl)-amino)phenoxy)-3-(4-phenylpiperazin-1-yl)-2-propanol (Compound 41)

0.2 ml of a 0.5 M 4-phenylpiperazine solution in DMPU is added to a solution of 19 mg (0.05 mmol) of substance 51 in N,N′-dimethylpropylurea (DMPU). The reaction mixture is kept for 18 hours at a temperature of 80° C. After cooling, 3.5 ml of tertiary butyl methyl ether is added, and the organic phase is extracted 5 times with 1.5 ml of H₂O and then evaporated in a vacuum. The remaining residue is chromatographed on 1.7 g (15 μM) of Lichrosphere Si60 (gradient: dichloromethane/hexane 1:1 to DCM and then dichloromethane/methanol 99:1 to 93:7). A product yield of 17 mg (64%) is achieved.

Similarly produced are also the following compounds:

No. Structure 96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

The following compounds are produced similarly to the described examples.

No. Structure Name 28

5-Bromo-N2-(4-(2-diethylaminoethylsulfonyl)phenyl)-N4-2-pro-pynyl-2,4-pyrimidine diamine 30

1-(4-[5-Bromo-4-(2-propynylamino)-2-py-rimidinyl]amino-phenylthio)-3-(diethylamino)-2-pro-panol 32

5-Bromo-N2-(3-phenylsulfonylphenyl)-N4-2-propynyl-2,4-py-rimidine diamine 33

N-[4-[[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]amino]-ben-zenesulfonyl]morpholine 41

1-(4-((5-Bromo-4-(2-propynyloxy)-pyrimidin-2-yl)-a-mino)phenoxy)-3-(4-phenylpiperazin-1-yl)-2-propanol 57

N-[5-Bromo-4-((2R)-1-hydroxy-4-methyl-2-butylamino)-2-py-rimidinyl]-indazol-5-amine 58

4-[[5-Fluoro-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-py-rimidinyl]amino]-benzenesulfonamide 59

4-[[5-Iodo-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-py-rimidinyl]amino]-benzenesulfonamide 62

4-[[5-Fluoro-4-(2-propynylamino)-2-pyrimidinyl]amino]-ben-zenesulfonamide 65

4-[[5-Ethyl-4-(2-propynylamino)-2-pyrimidinyl]amino]-ben-zenesulfonamide 66

1-[4-[(5-Iodo-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-py-rimidinyl)amino]phenyl]-ethanone 68

1-[4-[(5-Ethyl-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-py-rimidinyl)amino]phenyl]-ethanone 72

4-[[5-Bromo-4-(2-(2-oxo-imidazolin-1-yl)ethylamine)-2-py-rimidinyl]amino]-benzenesulfonamide 73

4-[[5-Bromo-4-(2,2,3,3,3-pentafluoropropyloxy)-2-py-rimidinyl]amino]-benzenesulfonamide 75

4-[[5-Bromo-4-(1,3-bisacetoxy-2-propyloxy)-2-py-rimidinyl]amino]-benzenesulfonamide 76

4-[[5-Bromo-4-(1,3-dihydroxy-2-propyloxy)-2-py-rimidinyl]amino]-benzenesulfonamide 79

N□-(5-Bromo-2-(4-sulfamoylphenyl)amino-pyrimidin-4-yl)-L-ala-nine amide 83

1-[4-[(5-Bromo-4-(2-propynylamino)-2-py-rimidinyl)amino]phenyl]-ethanol

The following compounds are produced analogously to the described synthesis processes according to Diagram 1 or 2:

All NMR spectra are measured in the indicated solvent or in DMSO.

Ex.-No. 37 38 39 5 6-H 8.34(s, 1H) 8.39(s, 1H) 8.30(s, 1H) 8.00(s, 1H) 2CH 12.88 9.28(s, 1H) 7.74(s, 1H) 7.52(d, 2H) (sb, 1H) 8.79(s, 1H) 7.44(d, 1H) 6.65(d, 2H) 8.07(s, 1H) 7.70(d, 1H) 7.22(d, 1H) 7.93(s, 1H) 8.04(d, 1H) 3.98(t, 2H) 7.41(d, 1H) 3.13(t, 2H) 7.56 2.99(s, 3H) 4CH (dd, 1H) 4.19(d, 2H) 4.16(d, 2H) 4.09(d, 2H) 3.22(sb, 1H) 3.28(sb, 1H) 3.09(s, 1H) NH 4.15 10.43(sb, 1H) 10.6(1H) 9.00(s, 1H) (dd, 2H) 8.45(sb, 1H) 8.75(1H) 8.96(s, 1H) 3.18(t, 1H) 7.31(t, 1H) 9.30(sb, 1H) 7.39(tb, 1H) Chromato EA + 0.5% — Crystallized — graphy TEA MeOH Yield 10% 36% 73% 20% Melting 231° C. >235° C. 237° C. 157° C. Point

Example No. 16 24 26 35 6-H 8.80(s, 1H) 8.30(s, 1H) 8.18(s, 1H) 8.14(s, 1H) 2CH 7.67(d, 2H) 7.94(d, 2H) 7.67(s, 1H) 8.28(s, 1H) 7.27(d, 2H) 7.63(d, 2H) 7.54(d, 1H) 7.98(d, 1H) 2.47(s, 3H) 7.24(t, 1H) 7.41(t, 1H) 6.92(d, 1H) 7.25(d, 1H) 4CH 4.17(dd, 2H) 4.17(dd, 2H) 4.20(dd, 2H) 4.14(dd, 2H) 3.75(t, 1H) 3.18(t, 1H) 3.12(sb, 1H) 3.04(sb, 1H) NH 10.55 10.45 9.78(sb, 1H) 9.58(sb, 1H) (sb, 1H) (sb, 1H) 7.95(sb, 1H) 7.46(sb, 1H) 8.68(sb, 1H) 8.22(sb, 1H) Chrom. — — — — Yield 94% 86% 73% 69% Melting 232-234° C. 160° C. 194° C. 143° C. Point

Example No. 27 36 34 21 6-H 8.18(s, 1H) 8.26(s, 1H) 8.25(s, 1H) 8.17(s, 1H) 2CH 8.73(s, 1H) 8.12(s, 1H) 8.16(s, 1H) 8.74(s, 1H) 7.62(d, 1H) 7.35- 7.43(d, 1H) 7.43(d, 1H) 7.72(t, 1H) 7.55(m, 3H) 7.52(t, 1H) 7.52(t, 1H) 8.31(d, 1H) 8.06(d, 1H) 8.01(d, 1H) 8.08(d, 1H) 2.78(m, 2H) 3.43(t, 2H) 1.35(mc, 2H) 3.70(t, 2H) 1.24(mc, 2H) 0.80(t, 3H) 4CH 4.18(dd, 2H) 4.21(d, 2H) 4.20(dd, 2H) 3.06(t, 1H) 4.21(d, 2H) 3.09(sb, 1H) 3.08(t, 1H) NH 10.02(s, 1H) 3.09(sb, 1H) 10.3(sb, 1H) 9.79(s, 1H) 7.49(sb, 1H) 9.68(sb, 1H) 8.13(sb, 1H) 7.55(tb, 1H) OH 7.30(sb, 2H) 4.90(sb, 1H) Chrom. — Cryst. EtOH — — Yield 69% 64% 87% 59% Melting 144° C. 219° C. 220° C. 192.5-193.5° C. Point

Example No. 31 25 23 11 6-H 8.25(s, 1H) 8.14(s, 1H) 8.25(s, 1H) 8.29(s, 1H) 2CH 7.65(d, 2H) 8.01(d, 2H) 7.86(d, 2H) 7.95(d, 2H) 7.24(d, 2H) 7.56(d, 2H) 7.51(d, 2H) 7.78(d, 2H) 3.19(d, 21.3Hz, 2H) 2.70(s, 3H) 7.38(t, 56.8Hz, 1H) 4CH 3.95(mc, 4H) 4.15(dd, 2H) 4.18(m, 2H) 4.19(d, 2H) 1.20(t, 6H) 3.14(t, 1H) 3.16(sb, 1H) 3.18(sb, 1H) NH 4.17(sb, 2H) 9.69(sb, 1H) 10.24(sb, 1H) 10.40(sb, 1H) 3.15(sb, 1H) 7.55(tb, 1H) 8.17(sb, 1H) 8.24(sb, 1H) 10.19(sb, 1H) 7.15(sb, 2H) 8.34(sb, 1H) Chrom. EA Cryst. DCM/MeOH — Cryst. Yield H/DIPE 95:5 85% DIPE/EtOH 23% 25% 17% Melting 198° C. 217-218° C. >235° C. >235° C. Point

Example No. 44 45 4 6-H 8.34(s, 1H) 8.34(s, 1H) 8.23n(sb, 1H) 2CH 7.93(d, 2H) 7.74(mc, 4H) 7.39(d, 2H) 7.79(d, 2H) 6.79(d, 2H) 4CH 4.20(sb, 2H) 4.55(q, 1H) 3.52-3.71(2H) 3.31(sb, 1H) 1.98(dq, 2H) 3.97(mc, 1H) 0.94(t, 3H) 1.96(mc, 1H) 3.61(s, 3H) 0.91(d, 3H) NH 11.03(sb, 1H) 10.60(s, 1H) 0.85(d, 3H) 9.04(sb, 1H) 7.97(d, 1H) 10.35(sb, 1H) 7.34(sb, 2H) 7.31(db, 2H) 7.76(sb, 1H) Chrom. Cryst. EtOH Cryst. EtOH — Yield 27% 48% 52% Melting 252° C. 235° C. 242-243° C. Point

Example

No. 10 15 3 19 6-H 8.27 (s,1H) 8.17 (s,1H) 7.97 (s,1H) 8.20-8.35 2H 7.80 7.60 (d,2H) 7.44 (d,2H) (2H) (mc,4H) 7.24 (d,2H) 6.67 (d,2H) 7.90 (sb,1H) 2.44 (s,3H) 7.50-7.64 (2H) 3.46 (t,2H) 4H 3.5-3.7 (2H) 3.50-3.65 3.70 (t,2H) 3.66. 40.1 (mc,1H) (4H) (mc,2H) 1.98 (mc,1H) 4.12 (mc,1H) 3-56-3.66 n.obs. 0.94 (d,3H) (4H) 2.04 0.90 (d,3H) 4.28 (mc,1H) NH (mc,1H) 9.95 (sb,1H) OH 0.97 (d,3H) 6.96 (sb,1H) 8.98 (sb,1H) 0.94 (d,3H) ca.4, sehr 5.97 (db,1H) 10.40 breit 8.90 (sb,1H) NH and OH (sb,1H) 4.80 (tb,2H) sind sehr 7.18(sb,2H) breit n. obs. Chrom. — — — Crystallized Water Yield 43% 27% 76% 52% Melting 252-253° C. 192-193° C. 257-258° C. 209-210° C. Point

Example

No. 9 14 55 50 6-H 8.30 (s,1H) 8.30 (s,1H) 8.11 (s,1H) 8.17 (s,1H) 2H 7.82 7.55 (d,2H) 7.87 (s,4H) 7.95 (d,2H) (mc,4H) 7.30 (d,2H) 2.50 (s) 7.86 (d,2H) 2.48 (s,3H) 2.50 (s) 4H 3.54-3.68 4.19 (mc,1H) 4.17 (dd,2H) 3.63 (4H) 3.61 (mc,4H) 3.13 (t,1H) (mc,4H) 4.24 (mc,1H) NH 4.24 9.73 (s,1H) 9.81 (s,1H) OH (mc,1H) 10.63 (sb,1H) 6.20 (s,1H) 7.58 (t,1H) 7.60 (sb,1H) 4.88 (t,2H) 10.59 (b,1H) 4.4 (b) 7.2 (sb) 6.1 (sb) Chrom. Crystallized Crystallized — MeOH MeOH/DIPE Yield 24% 91% 27% 56% Melting 247-248° C. 233-234° C. 228-229° C. 241° C. Point

Example

No. 46 13 52 53 6-H 8.07s,1H) 8.00 (s,1H) 8.09 (s,1H) 8.11 (s,1H) 2H 7.91 (d,2H) 7.68 (d,2H) 7.88 (s,4H) 7.86 (s,4H) 7.69 (d,2H) 7.18 (d,2H) not obs. 2.44 (s,3H) 4H 3.30 (t,2H) 3.54 (q,2H) 3.32 (t,2H) 3.62 (mc,2H) n.obs.(mc,1 2.53 (t,2H) 1.20 (mc,1H) 4.06 (mc,1H) H) 2.40-2.45 0.44 (mc,2H) 2.02 (mc,1H) 0.45 (4H) 0.30 (mc,2H) 0.97 (d,3H) (mc,2H) 3.58 (t,4H) 0.92 (d,3H) NH 0.30 9.70 (s,1H) 9.70 (s,1H) OH (mc,2H) 9.20 (sb,1H) 7.21 (t,1H) 6.24 (d,1H) 6.81 (tb,1H) 4.80 (sb,1H) 9.94 (s,1H) 7.21 (t,1H) 7.18 (s,2H) Chrom. H/EA 1:2 — — H/EA 1:2 Yield 20% 28% 53% 9% Melting 256° C. 185-186° C. 183° C. 170° C. Point

Example

No. 1 54 12 60 6-H 7.96 (s,1H) 8.22 (s,1H) 8.03 (s,1H) 8.10 (s,1H) 2H 7.43 (d,2H) 7.93 (d,2H) 7.68 (d,2H) 7.92 (d,2H) 6.67 (d,2H) 7.85 (d,2H) 7.19 (d,2H) 7.66 (d,2H) 2.43 (s,3H) not. obs. 2.74 (t,2H) 4H 1.20 (d,3H) 4.26 (d,2H) 1.20 (d,3H) 3.61 (mc,2H) 4.38 3.12 (sb,1H) 4.42 (mc,1H) 4.04 (mc,1H) (mc,1H) 3.37 (dd,1H) 2.01 (mc,1H) 3.37 (dd,1H) 3.50 (dd,1H) 0.94 (d,3H) 3.48 (dd,1H) 3.34 (s,3H) 0.91 (d,3H) NH 3.28 (s,3H) 9.78 (s,1H) 9.26 (s,1H) 9.72 (s,1H) 8.92 (sb,1H) 7.65 (s,1H) 8.81 (sb,1H) 6.27 (d,1H) OH 7.21 (t,1H) 6.42 (d,1H) 4.80 (sb,1H) 6.20 (tb,1H) 4.70 (sb,1H) Chrom. Crystallized Crystallized Crystallized EA DIPE/MeOH EA Yield 64% 52% 36% Melting 165.5- 210° C. 91° C. 150-151° C. Point 166° C.

Example

No. 7 17 2 18 6-H 8.32 (s,1H) 8.08 (s,1H) 7.95 (s,1H) 8.32 (s,1H) 4CH 1.22 (d,3H) 1.21 (d,3H) 3.50 (q,2H) 3.10 (m,2H) 4.46 4.53 (mc,1H) 2.50 (t,2H) 3.52 (m,4H) (mc,1H) 3.41 (dd,1H) 2.40 (t,4H) 3.77-3.97 3.40 (dd,1H) 3.51 (dd,1H) 3.59 (t,4H) (6H) 3.57 (dd,1H) 3.27 (s,3H) 2CH 3.28 (s,3H) 8.53 (s,1H) 7.45 (d,2H) 7.80 (s,4H) 7.40 (d,1H) 6.66 (d,2H) 8.40 (s,1H) 7.50 (t,1H) 7.55-7.70 7.86 (d,1H) (2H) 3.40 (t,2H) 7.85 (d,1H) 3.68 (t,2H) 3.48 (m,2H) NH 9.65 (sb,1H) 8.94 (sb,1H) 3.70 (m,2H) 10.79 6.47 (db,1H) 8.79 (sb,1H) OH (sb,1H) 4.84 (tb,1H) 6.70 (tb,1H) 11.16 (sb,1H) 7.84 (db,1H) 10.60 (sb,1H) 7.31 (sb,2H) 8.20 (sb,1H) Chrom. — — Crystall. MeOH Yield 25% 10% 62% 50% Melting 247° C. Dec. 201-202° C. 227.5- 245° C. Dec. Point 228.5° C.

Example

No. 8 (D₂O) 6-H 8.14 (s,1H) 4CH 3.06 (sb,2H) 3.39 (t,4H) 3.71 (sb,2H) 3.85 (sb,2H) 3.94 (t,2H) 2CH 8.00 (d,2H) 7.72 (d,2H NH OH Chrom. Cryst. Water Yield 25% Melting >275° C. Point

Example

No. 47 6 22 84 5-H 8.74 (s,1H) 8.31 (s,1H) 8.31 (s,1H) 8.47 (s,1H) 2CH 7.87 (d,2H) 7.47 (d,2H) 7.76 (d,2H) 4.48 (t,2H) 7.74 (d,2H) 6.71 (d,2H) 7.72 (d,2H) 2.01 (mc,2H) 2.58 (s,3H) 2.44 (mc,2H) 4CH 4.50 (t,2H) 5.04 (d,2H) 5.05 (d,2H) 2.03 (mc,2H) 3.59 (t,1H) 2.57 (t,1H) 7.91 (d,2H) 2.44 (mc,2H) 2NH 10.14 (s,1H) 9.02 (sb,1H) 7.47 (sb,1H) 7.85 (d,2H) 7.21 (s,2H) 9.40 (sb,1H) 2.50 (s) 10.19(s,1H) Chrom. MeOH/DCM — — Yield 1:9 66% 8% 11% 4% Melting 186-187° C. 146° C. 165-166° C. 152° C. Point

Example

No. 86 77 5-H 8.47 (s,1H) 8.48 (s,1H) 2CH 4.07 (mc,2H) 5.52 (m,1H) 3.81 (mc,2H) 3.68 (d,4H) 3.60 (mc,2H) 3.48 (mc,4H) 4CH 3.48 (mc,2H) 1.09 (t,6H) 3.41 (t,2H) 7.84 (d,2H) 1.07 (t,3H) 2NH 7.84 (d,2H) 7.74 (d,2H) 7.91 (d,2H) 8.05 (vb) 10.18 (s,1H) 3.40 (vb) Chrom. — — Yield 2% 74% Melting 85° C. 132° C. Point

Example

No. 40 20 6-H 8.36 (s,1H) 8.40 (s,1H) 2CH 7.60 (d,1H) 7.23 (s,1H) 6.91 (d,1H) 6.42 (d,1H) 4.28 (dd,1H) 7.06 (t,1H) 3.79 (dd,1H) 7.18 (d,1H) 3.31 (m,1H) 2.84 (dd,1H) 2.70 (dd,1H) 4CH 5.07 (d,12H) 5.12 (d,2H) 3.65 (t,1H) 3.60 (sb,1H) NH 9.65 (sb,1H) 9.60 (sb,1H) OH 9.21 (sb,1H) Chrom. H/EA 1:3 krist. DIPE Yield 0.5% TEA 35% 38% Melting 140-141° C. 174° C. Point

Example

No. 49 48 29 42 6-H 8.14 (s,1H) 8.10 (s,1H) 8.09 (s,1H) 7.87 (d,3.4,1H) 2H 7.88 (d,2H) 7.92 (d,2H) 8.50 (s,1H) 7.51 (d.2H) 7.69 (d,2H) 7.66 (d,2H) 7.86 (d,1H) 6.66 (d,2H) not. obs. 7.50 (t,1H) 2.74 (t,2H) 7.40 (d,1H) 4H 3.41 (q,2H) 3.61 (mc,2H) 3.40 (t,2H) 4.13 (dd,2H) 2.20 (t,2H) 4.04 (mc,1H) 3.52-3.73 3.08 (t,1H) 1.81 (q,2H) 2.01 (mc,1H) (4H) 0.94 (d,3H) 4.09 (mc,1H) 0.91 (d,3H) 1.98 (mc,1H) 0.97 (d,3H) NH 9.64 (s,1H) 9.72 (s,1H) 0.89 (d,3H) 8.76 (s,1H) 7.64 (t,1H) 7.65 (s,1H) 9.68 (s,1H) 7.74 (tb,1H) OH 3.5(vb 6.27(d,1H) 6.17(d,1H) 8.88(s,1H) 4.80 (sb,1H) 4.74 (t,1H) 4.70 (sb,1H) 4.93 (t,1H) Chrom. — Cryst. DCM/EA 2:1 H/EA 1:2 MeOH/DIPE Yield 9% 16% 26% 29% Melting 262° C. 150-151° C. 163° C. Point

Exam-

ple No. 43 55 89 88 6-H 7.93 (s, 1H) 8.11(s, 1H) 8.36(s,1H) 8.29(s, 1H) 2H 7.52(d, 2H) 7.87 (s, 4H) 7.7-7.8(5H) 7.73(d, 2H) 6.68(d, 2H) 2.50(s) 7.57(d, 2H) 4H 3.09(s, 1H) 4.19(mc, 1H) 3.66(mc, 2H) 3.7-3.9(2H) 4.14(d, 2H) 3.61(mc, 4H) 4.04(m, 1H) 5.19(m, 1H) 1.99(mc, 1H) 7.2-7.4(5H) 0.94(d, 3H) 0.89(d, 3H) NH 8.98(sb, 2H) 9.73(s, 1H) 11.11(sb, 1H) 10.50(s, 1H) 7.50(s, 1H) 6.20(s, 1H) 5.029(vb) OH 4.88(t, 2H) 7.34(sb, 2H) n. obs. Chrom. H/EA 1:2 Cryst. MeOH/ — — DIPE Yield 35% 27% 74% 27% Melting 168° C. 228° C. 248° C. Dec. 159° C. Dec. Point

Exam-

ple No. 87 92 91 96 6-H 8.09(s, 1H) 8.10(s, 1H) 8.09(s, 1H) 8.06(s, 1H) 2H 7.90(d, 2H) 7.91(d, 2H) 7.98(d, 2H) 7.88(d, 2H) 7.82(d, 2H) 7.63(d, 2H) 7.61(d, 2H) 7.69(d, 2H) not. obs 2.39(d, 3H) 2.54(s, 6H) 4H 3.69(td, 2H) 1.21(d, 3H) 1.20(d, 3H) 2.41(m, 2H) 2.84(t, 2H) 4.45(mc, 1H) 4.46(mc, 1H) 1.62(m, 4H) 7.60(s, 1H) 3.38(dd, 1H) 3.47(dd, 1H) 2.41(m, 2H) 6.86(s, 1H) 3.51(dd, 1H) 3.51(dd, 1H) 5.07(s, 2H) 3.38(s, 3H) NH 7.34(tb, 1H) 9.73(sb, 1H) 9.81(sb, 1H) 7.32(s, 5H) 9.72(s, 1H) 7.20(q, 1H) 6.58(db, 1H) 9.64(s, 1H) 7.16(sb, 2H) OH 11.91(sb, 1H) 6.57(d, 1H) Chrom. — H bis H/EA 1:1 H bis H/EA — Yield 16% 21% 1:1 33% 7% Melting 210° C. 167-168° C. 105° C. 202° C. Point

Exam-

ple No. 97 98 90 85 6-H 8.07(s, 1H) 8.10(s, 1H) 8.30(s, 1H) 2H 7.87(s, 4H) 7.86(mc, 4H) 7.95(d, 2H) 2.50(s, 3H) n. obs. 7.69(d, 2H) 2.48(s, 3H) 4H 3.41(m, 2H) 3.68(t, 2H) 3.50(q, 2H) 1.61(m, 4H) 2.68(t, 2H) 1.87(m, 2H) 2.41(m, 2H) 4.08(q, 2H) 2.38(t, 2H) 5.07(s, 2H) 1.17(t, §H) 4.03(q, 2H) 1.13(t, 3H) NH 7.32(s, 5H) 9.74(s, 1H) 10.86(s, 1H) 9.70(s, 1H) 7.18(t, 1H) 8.28(sb, 2H) 7.19(t, 1H) Chrom. — — — Yield 23% 32% 53% Melting 152° C. 172 184° C. Point

Exam-

ple No. 63 94 93 80 9.73(s, 1H) 10.91(s, 1H) 10.80(s, 1H) 10.88(s, 1H) 8.25(s, 1H) 8.34(s, 1H) 8.30(s, 1H) 8.40(s, 1H) 7.95(d, 2H) 7.80(s, 4H) 7.81(d, 2H) 8.29(m, 1H) 7.67(d, 2H) 7.30(s, 2H) 7.65(d, 2H) 7.79(s, 4H) 7.21(s, 3H) 4.35(m, 1H) 7.30(m, 8H) 7.31(s, 2H) 4.12(s, 2H) 3.58(m, 2H) 4.95(d, 1H) 4.75(dd, 1H) 3.12(s, 1H) 2.47(m, 2H) 4.38(m, 1H) 3.65(m, 1H) 2.03(s, 3H) 3.59(d, 1H) 3.49(m, 1H) 1.91(m, 2H) 2.10(m, 2H) Yield 61% 24% 70% 51% Melting 220 168 243 Point Mass 428(EI) 462(ES) 494(ES) 427(EI)

Exam- ple No. 120 121 9.65(s, 1H) 9.68(s, 1H) 8.12(s, 1H) 8.11(s, 1H) 7.89(d, 2H) 7.93(t, 1H) 7.65(d, 2H) 7.90(d, 2H) 7.15(s, 2H) 7.65(d, 2H) 6.06(d, 1H) 7.15(s, 2H) 4.71(t, 1H) 7.07(t, 1H) 4.18(m, 1H) 3.65(m, 2H) 3.67(t, 1H) 3.56(s, 3H) 0.95(s, 9H) 3.07(q, 2H) 2.45(t, 2H) 2.30(t, 2H) 1.65(p, 2H) Yield 49% 24% Melting Point Mass 445(EI) 516(EI)

Exam- ple No. 122 123 11.30(s, 1H) 10.79(s, 1H) 8.11(d, 1H) 8.35(s, 1H) 7.85(d, 2H) 8.25(S, 1H) 7.72(d, 2H) 7.80(s, 4H) 7.31(s, 2H) 7.30(s, 2H) 6.71(d, 1H) 3.41(m, 2H) 3.85(m, 8H) 2.22(t, 2H) 1.60(m, 4H) 1.30(m, 2H) Yield 80% 73% Melting 252 Point Mass 334(EI) 459(EI)

Exam- ple No. 95 124 11.19(s, 1H) 9.62(s, 1H) 8.37(s, 1H) 8.04(s, 1H) 8.11(d, 1H) 7.88(m, 3H) 7.80(s, 4H) 7.66(d, 2H) 7.31(s, 2H) 7.13(s, 3H) 3.91(m, 1H) 3.58(s, 3H) 1.89(m, 4H) 3.40(m, 2H) 1.67(m, 1H) 3.05(m, 2H) 1.55(m, 2H) 2.25(m, 2H) 1.34(m, 2H) 2.05(m, 2H) 1.15(m, 1H) 1.60(m, 5H) 1.32(m, 3H) Yield 29% 25% Melting 255 Point Mass 425(EI) 557(ES)

Exam- ple No. 125 126 9.62(s, 1H) 10.91(s, 1H) 8.04(s, 1H) 8.38(s, 1H) 7.86(d, 2H) 7.83(d, 2H) 7.66(d, 2H) 7.77(d, 2H) 7.12(s, 3H) 7.28(s, 2H) 3.58(s, 3H) 7.04(d, 1H) 3.40(m, 2H) 6.40(br, 3H) 2.30(t, 2H) 4.35(m, 1H) 1.60(m, 4H) 3.87(m, 1H) 1.32(m, 2H) 3.60(d, 2H) 3.41(dd, 1H) 3.28(dd, 1H) Yield 27% 46% Melting 218 Point Mass 471(EI) 449(EI)

Exam- ple No. 127 128 9.96(s, 1H) 9.60(s, 1H) 8.12(s, 1H) 8.05(s, 1H) 7.85(d, 2H) 7.90(d, 2H) 7.69(d, 2H) 7.69(d, 2H) 7.20(s, 2H) 7.42(d, 1H) 6.78(d, 1H) 7.16(m, 3H) 4.35(m, 1H) 4.57(t, 2H) 3.48(m, 2H) 3.70(m, 1H) 1.65(m, 7H) 3.4(m, 5H) 1.10(m, 6H) 2.10(t, 2H) 1.55(m, 4H) 1.30(m, 2H) Yield 18% 94% Melting 220 Point Mass 485(EI) 531(ES)

Exam- ple No. 129 130 9.67(s, 1H) 9.65(s, 1H) 8.07(s, 1H) 8.08(s, 1H) 7.87(d, 2H) 7.87(d, 2H) 7.75(d, 2H) 7.64(d, 2H) 7.13(s, 2H) 7.14(s, 2H) 6.40(d, 1H) 6.53(d, 1H) 4.91(br, 1H) 4.62(d, 1H) 4.23(m, 1H) 3.90(br, 1H) 3.52(m, 2H) 3.40(br, 1H) 1.21(d, 3H) 1.88(m, 4H) 1.50(m, 2H) 1.30(m, 2H) Yield 61% 58% Melting 259 262 Point Mass 403(EI) 443(EI)

Exam-

ple No. 131 132 133 134 9.62(s, 1H) 9.70(s, 1H) 9.69(s, 1H) 10.85(s, 1H) 8.08(s, 1H) 8.11(s, 1H) 8.11(s, 1H) 8.31(s, 1H) 7.92(d, 2H) 7.90(d, 2H) 7.88(d, 2H) 7.90(d, 1H) 7.67(d, 2H) 7.60(d, 2H) 7.66(d, 2H) 7.85(d, 2H) 7.23(s, 2H) 7.21(q, 1H) 7.15(s, 2H) 7.75(d, 2H) 6.75(t, 1H) 5.25(d, 1H) 6.52(d, 1H) 7.54(s, 1H) 3.22(d, 2H) 4.77(t, 1H) 4.35(dd, 1H) 3.90(m,1H) 1.95(s, 3H) 4.02(m, 1H) 2.29(m, 1H) 3.38(t, 2H) 1.60(m, 12H) 3.60(m,2H) 1.07(d, 3H) 2.78(br, 2H) 2.39(d, 3H) 0.91(d, 3H) 1.50(m, 11H) 2.02(m, 1H) 0.95(dd, 6H) Yield 9% 42% 25% 64% Melting 229 141 Point Mass 491(EI) 443(EI) 444(FAB)

Exam- ple No. 135 136 10.01(s, 1H) 9.70(s, 1H) 8.28(s, 1H) 8.11(s, 1H) 7.81(d, 2H) 7.90(d, 2H) 7.71(t, 1H) 7.64(d, 2H) 7.63(d, 2H) 7.35(t, 1H) 7.45(br, 1H) 6.55(d, 1H) 4.34(dt, 2H) 4.65(t, 1H) 3.32(t, 2H) 4.45(m, 1H) 2.71(br, 2H) 3.53(m, 1H) 3.44(m, 6H) 2.75(q, 2H) 1.20(d, 3H) Yield 34% 53% Melting Point Mass 570(ES) 460(ES)

Exam- ple No. 137 138 9.65(s, 1H) 9.70(s, 1H) 9.58(s, 1H) 8.10(s, 1H) 8.10(s, 1H) 7.89(d, 2H) 7.85(d, 2H) 7.63(d, 2H) 7.68(d, 2H) 7.39(t, 1H) 7.40(m, 2H) 6.68(d, 1H) 7.18(m, 4H) 4.34(dd, 1H) 6.94(t, 1H) 3.36(m, 3H) 6.75(d, 1H) 2.25(q, 2H) 4.40(m, 3H) 2.29(m, 1H) 2.05(m, 1H) 1.05(dd, 6H) 0.96(dd, 6H) Yield 59% 57% Melting Point Mass 549(ES) 488(ES)

Exam-

ple No. 139 140 141 142 9.82(s, 1H) 9.82(s, 1H) 9.58(s, 1H) 9.62(s, 1H) 8.15(s, 1H) 8.08(s, 1H) 8.12(s, 1H) 8.97(s, 1H) 7.82(d, 2H) 7.96(d, 2H) 7.83(d, 2H) 7.87(d, 2H) 7.64(d, 2H) 7.75(t, 1H) 7.68(d, 2H) 7.67(d, 2H) 7.39(t, 1H) 7.62(d, 2H) 7.15(s, 2H) 7.14(s, 2H) 6.55(d, 1H) 7.30(t, 1H) 5.92(s, 1H) 6.36(d, 1H) 4.64(t, 1H) 4.64(t, 1H) 5.28(t, 1H) 4.81(t, 1H) 4.50(t, 1H) 4.14(m, 2H) 3.50(d, 2H) 4.32(m, 1H) 3.65(s, 3H) 3.35(m, 2H) 1.42(s, 6H) 3.47(m, 2H) 3.4(m, 2H) 3.16(m, 1H) 1.52(m, 3H) 2.75(m, 2H) 2.75(q, 2H) 0.90(d, 3H) 2.35(m, 1H) 0.86(d, 3H) 1.00(dd, 6H) Yield 20% 63% 23% 8% Melting Point Mass 502(ES) 382(ES) 415(EI) 443(EI)

Exam-

ple No. 143 144 145 78 10.6(s, 1H) 10.11(s, 1H) 11.05(s, 1H) 9.69(s, 1H) 8.28(s, 1H) 8.45(s, 1H) 8.32(s, 1H) 8.06(s, 1H) 8.30(m, 5H) 7.86(d, 2H) 8.08(d, 1H) 7.88(d, 2H) 7.48(d, 1H) 7.78(d, 2H) 7.80(m, 4H) 7.63(d, 2H) 7.20(s, 1H) 7.15(br, 2H) 7.30(br, 2H) 7.18(s, 2H) 4.05(br, 1H) 5.32(m, 1H) 3.88(m, 1H) 7.10(t, 1H) 3.60(br, 2H) 3.91(m, 2H) 3.65(m, 1H) 6.65(d, 1H) 2.01(m, 1H) 3.53(m, 2H) 1.95(m, 2H) 4.47(m, 1H) 0.90(m, 6H) 2.05(m, 2H) 1.69(m, 2H) 3.97(m, 1H) 1.70(m, 2H) 1.35(m, 4H) 2.98(m, 2H) 2.00(m, 4H) 1.40(m, 8H) 0.85(t, 3H) Yield 13% 47% 42% 20% Melting Point Mass 392(EI) 428(EI) 441(EI) 541(ES)

Exam-

ple No. 146 147 148 149 11.13(s, 1H) 11.18(s, 1H) 11.15(s, 1H) 9.19(s, 1H) 8.38(s, 1H) 8.35(s, 1H) 8.35(s, 1H) 8.30(s, 1H) 7.92(d, 2H) 7.90(s, 4H) 7.90(d, 2H) 8.02(s, 1H) 7.75(m, 3H) 7.62(d, 1H) 7.65(m, 3H) 7.62(m, 1H) 4.04(m, 1H) 4.02(m, 1H) 4.01(m, 1H) 6.85(d, 1H) 3.80(s, 3H) 3.62(m, 2H) 3.60(m, 6H) 6.05(d, 1H) 3.65(m, 2H) 3.02(s, 3H) 2.85(m, 4H) 4.03(m, 1H) 2.00(m, 1H) 2.00(m, 1H) 2.00(m, 1H) 3.56(m, 2H) 0.96(d, 3H) 0.95(d, 3H) 0.95(d, 3H) 1.96(m, 1H) 0.89(d, 3H) 0.89(d, 3H) 0.85(d, 3H) 0.97(d, 3H) 0.90(d, 3H) Yield 86% 33% 79% 42% Melting 225 211 232 241 Point Mass 408(EI) 428(EI) 501(EI) 411(ES)

Exam-

ple No. 150 151 152 153 11.19(s, 1H) 10.96(s, 1H) 9.50(s, 1H) 12.90(s, 1H) 10.80(s, 1H) 8.35(s, 1H) 8.08(s, 1H) 9.45(s, 1H) 8.30(m, 2H) 7.95(m, 2H) 7.75(m, 5H) 8.52(s, 1H) 7.85(d, 1H) 7.65(m, 3H) 6.17(d, 1H) 8.05(s, 1H) 7.72(d, 1H) 4.04(m, 1H) 4.80(br, 1H) 7.82(d, 1H) 7.20(d, 1H) 3.62(m, 2H) 4.64(br, 2H) 7.50(d, 1H) 4.02(m, 1H) 2.00(m, 1H) 4.05(m, 1H) 7.32(t, 1H) 3.60(m, 2H) 0.90(M, 6H) 3.94(m, 1H) 6.11(d, 1H) 2.00(m, 1H) 3.52(m, 6H) 4.72(s, 1H) 1.01(d, 3H) 2.01(m, 1H) 4.10(s, 1H) 0.90(d, 3H) 0.93(dd, 6H) 3.60(m, 2H) 2.01(m, 1H) 0.99(d, 3H) 0.92(d, 3H) Yield 27% 65% 85% 9% Melting 231 Point Mass 420(ES) 395(ES) 468(ES) 395(ES)

Exam-

ple No. 154 155 156 157 10.91(s, 1H) 11.05(s, 1H) 10.51(s, 1H) 15.5o(s, 1H) 8.38(s, 1H) 8.34(m, 2H) 8.22(s, 1H) 9.50(s, 1H) 7.90(d, 1H) 7.75(m, 3H) 7.71(d, 1H) 8.40(s, 1H) 7.80(m, 4H) 7.52(t, 1H) 7.27(m, 1H) 8.11(s, 1H) 7.05(d, 1H) 4.04(m, 1H) 6.86(m, 2H) 7.80(d, 1H) 4.50(s, 2H) 3.85(s, 3H) 6.06(s, 2H) 7.53(d, 1H) 4.04(m, 1H) 3.65(m, 2H) 3.96(m, 1H) 6.16(d, 1H) 3.62(m, 2H) 2.00(m, 1H) 3.62(m, 2H) 4.78(br, 1H) 1.96(m, 1H) 0.94(d, 3H) 1.99(m, 1H) 4.03(m, 1H) 0.93(d, 3H) 0.85(d, 3H) 0.90(m, 6H) 3.60(m, 2H) 0.85(d, 3H) 2.01(m, 1H) 0.91(dd, 6H) Yield 90% 48% 77% 21% Melting 170 181 177 196 Point Mass 381(ES) 409(ES) 394(EI) 391(EI)

Exam-

ple No. 158 159* 160* 161* 10.80(s, 1H) 9.65 9.65 7.92(s, 1H) 8.31(s, 1H) (s, 1H, 1+2) (s, 1H, 1+2) 7.84(d, 2H) 7.97(d, 2H) 8.08 8.08 7.58(d, 2H) 7.88(m, 3H) (s, 1H, 1+2) (s, 1H, 1+2) 3.72(m, 1H) 7.52(m, 5H) 7.88 7.88 3.35(m, 2H) 4.01(m, 1H) (d, 2H, 1+2) (d, 2H, 1+2) 3.10(m, 1H) 3.62(m, 2H) 7.65 7.65 2.91(m, 2H) 2.00(m, 1H) (d, 2H, 1+2) (d, 2H, 1+2) 2.00(m, 2H) 0.91(m, 6H) 7.15 7.15 1.89(m, 2H) (s, 1H, 1+2) (s, 1H, 1+2) 1.66(m, 4H) 6.62(d, 1H, 2) 6.62(d, 1H, 2) 1.39(m, 5H) 6.40(d, 1H, 1) 6.40(d, 1H, 1) 4.05(m, 1H, 1) 4.05(m, 1H, 1) 3.89(m, 1H, 2) 3.89(m, 1H, 2) 2.30-1.20 2.30-1.20 (m, 15H, 1+2) (m, 15H, 1+2) Yield 37% 21% 14% 8% Melting 199 >300 Point Mass 469(EI) 468(EI) 468(EI) 508(EI)

  

Ex. No. 162 163* 11.25(s, 1H) 10.95(s, 1H) 9.40(s, 1H) 10.72(s, 1H) 8.47(s, 1H) 9.47(br, 2H) 8.29(s, 1H) 9.30(br, 2H) 7.63(s, 1H) 8.32(2xs, 2H) 7.43(d, 1H) 8.08(d, 1H) 7.07(m, 3H) 7.88(d, 2H) 4.06(m, 1H) 7.75(m, 6H) 3.63(m, 2H) 7.30(br, 4H) 1.98(m, 1H) 6.95(d, 1H) 0.95(d, 3H) 4.12(m, 1H) 0.85(d, 3H) 3.98(m, 1H) 3.30(m, 1H) 3.10(m, 1H) 2.69(m, 2H) 2.25(m, 2H) 1.80(m, 18H) 1.01(m, 4H) 0.72(m, 4H) Yield 16% 33% Melting 195 Point Mass 446(ES) 480(EI)

 

Ex. No. 164 165 9.65(s, 1H) 8.54(s, 1H) 8.10(s, 1H) 7.82(d, 1H) 7.45(m, 2H) 6.20(d, 1H) 4.70(t, 1H) 4.10(m, 1H) 3.60(m, 2H) 3.15(s, 3H) 2.00(m, 1H) 0.96(d, 3H) 0.89(d, 3H) Yield 14% 51% Melting 162-164 Point Mass 429(ES) 462(EI)

 

Exam- ple No. 166 167* 10.90(s, 1H) 11.15(br, 1H) 8.95(s, 1H) 10.90(s, 1H) 7.93(m, 2H) 9.75(br, 2H) 7.25(m, 3H) 8.35(s, 1H) 6.30(s, 1H) 7.78(m, 4H) 6.00(d, 1H) 7.30(br, 2H) 4.75(tr, 1H) 4.15(m, 1H) 4.05(m, 1H) 3.50(m, 5H) 3.60(m, 2H) 2.85(s, 6H) 2.00(m, 1H) 1.90(m, 8H) 1.00(m, 6H) Yield 6% 16% Melting 256 Point Mass 390(ES) 512(ES)     

Exam- ple No. 168* 169 11.30(br, 2H) 9.05(br, 1H) 11.08(s, 1H) 8.85(s, 1H) 10.92(s, 1H) 8.11(d, 1H) 9.90(s, 1H) 7.97(s, 1H) 9.70(s, 1H) 7.47(dd, 1H) 8.36(2xs, 2H) 6.80(d, 1H) 8.20(d, 1H) 5.95(d, 1H) 7.93(d, 2H) 4.80(br, 2H) 7.75(m, 6H) 3.90(m, 2H) 7.35(br, 4H) 3.45(m, 6H) 7.10(d, 1H) 2.00(m, 1H) 4.15(m, 1H) 0.90(m, 6H) 3.98(m, 1H) 3.64(m, 8H) 3.40(m, 5H) 3.10(m, 5H) 1.95(m, 26H) Yield 58% 60% Melting 261 Point Mass 538(ES) 484(ES)

Exam-

ple No. 170* 171 172 173 11.05(s, 1H) 10.45(s, 1H) 11.05(s, 1H) 8.90(s, 1H) 10.90(s, 1H) 8.25(s, 1H) 8.35(m, 2H) 8.72(s, 1H) 10.6(br, 2H) 8.00(br, 1H) 7.82(d, 1H) 7.95(s, 1H) 8.35(2xs, 2H) 7.85(d, 2H) 7.65(d, 2H) 7.18(m, 1H) 8.15(d, 1H) 7.75(d, 2H) 7.50(t, 1H) 7.05(dd, 1H) 7.80(m, 8H) 7.45(br, 1H) 4.05(m, 1H) 6.75(d, 1H) 7.30(br, 4H) 3.60(m, 5H) 3.62(m, 2H) 5.99(d, 1H) 7.05(m, 1H) 3.35(m, 2H) 2.00(m, 1H) 4.74(t, 1H) 4.25(m, 1H) 2.80(m, 2H) 0.96(d, 3H) 4.03(m, 1H) 3:95(m, 2H) 2.41(t, 2H) 0.85(d, 3H) 3.70 .(s, 3H) 3.65(m, 1H) 1.90(m, 2H) 3.60(m, 2H) 3:20(m, 10H) 2.00(m, 1H) 1.90(m, 24H) 0.90(m, 6H) Yield 64% 7% 65% 40% Melting 226 164 206 144 Point Mass 525(ES) 488(ES) 395(ES) 397(ES)

Exam- ple No. 174* 175* 11.05(m, 3H) 11.15(br, 1H) 10.48(s, 1H) 11.05(s, 2H) 8:38(s, 2H) 10.65(br, 1H) 7.80(m, 8H) 8.30(s, 2H) 7.80(br, 4H) 8.13(m, 2H) 7.10(s, 1H) 7.88(m, 8H) 6.95(s, 1H) 7.30(br, 4H) 4.42(m, 2H) 4.40(m, 2H) 4.1.8(m, 2H) 4.00(br, 2H) 3.70-2.90 3.70-2.90 (m, 10H) (m, 10H) 2.40-1.60 2.40-1.40 (m, 20H) (m, 20H) Yield 95% 51% Melting Point Mass 511(ES) 511(ES)

Exam- ple No. 176 177 8.00(s, 1H) 9.65(s, 1H) 7.80(m, 4H) 8.08(s, 1H) 4.48(m, 1H) 7.85(d, 2H) 3.65(d, 2H) 7.65(d, 2H) 1.75(m, 1H) 7.40(br, 1H) 1.59(m, 2H) 7.15(s, 2H) 1.01(d, 3H) 3.55(m, 2H) 0.92(d, 3H) 2.55(m, 2H) 2.15(m, 2H) 1.80(m, 3H) 1.65(m, 1H) Yield 3% 8% Melting Point Mass 443(EI) 456(EI)

Exam-

ple No. 178 179 180 181 9.49(s, 1H) 9.61(s, 1H) 9.65(s, 1H) 9.71(s, 1H) 8.25(s, 1H) 8.08(s, 1H) 8.11(s, 1H) 8.06(s, 1H) 7.80(m, 4H) 7.88(d, 2H) 7.81(s, 2H) 7.90(d, 2H) 7.32(br, 2H) 7.65(d, 2H) 7.63(d, 2H) 7.61(d, 2H) 4.03(m, 2H) 7.60(t, 1H) 7.15(s, 2H) 7.37(t, 1H) 3.75(m, 1H) 7.15(s, 2H) 6.64(d, 1H) 6.56(d, 1H) 3.35(m, 2H) 3.45(m, 2H) 4.28(m, 3H) 4.66(m, 2H) 1.80(m, 2H) 2.40(t, 2H) 2.00(m, 1H) 3.90(m, 1H) 1.40(m, 2H) 2.20(s, 6H) 1.98(s, 3H) 3.39(m, 3H) 1.75(t, 2H) 0.98(d, 3H) 2.78(q, 2H) 0.93(d, 3H) 1.96(m, 4H) 1.56(m, 2H) 1.29(m, 2H) Yield 17% 9% 27% 24% Melting Point Mass 427(EI) 428(EI) 472(ES) 486(ES)

Example

No. 182 183 184 185 9.68 (s, 1H) 10.97 (s, 1H) 11.06 (s, 1H) 11.01 (s, 1H) 9.47 (s, 1H) 8.30 (s, 1H) 8.04 (m, 1H) 8.38 (s, 1H) 8.10 (s, 1H) 8.02 (d, 1H) 7.82 (m, 2H) 7.82 (s, 4H) 7.81 (d, 2H) 7.81 (m, 4H) 7.70 (m, 2H) 7.40 (d, 1H) 7.67 (d, 2H) 7.30 (s, 2H) 7.30 (s, 2H) 7.32 (s, 2H) 7.14 (s, 2H) 4.14 (m, 1H) 6.72 (m, 1H) 4.20 (m, 1H) 6.76 (m, 3H) 1.80 (m, 12H) 3.75 (m, 5H) 3:70 (m, 2H) 4.47 (m, 2H) 1.88 (m, 2H) 0.97 (s, 9H) 4.30 (m, 1H) 1.48 (m, 2H) 3.65 (s, 6H) 3.54 (s, 3H) 1.99 (m, 1H) 0.98 (d, 3H) 0.92 (d, 3H) Yield 57% 78% 26% 76% Melting Point Mass 639 (ES) 439 (EI) 348 (EI) 445 (EI)

Example

No. 186 187 188 189 9.71 (s, 1H) 7.75 (s, 1H) 10.60 (s, 1H) 11.19 (s, 1H) 8.11 (s, 1H) 7.65 (d, 2H) 8.29 (s, 1H) 8.03 (d, 1H) 7.90 (d, 2H) 7.58 (d, 2H) 7.79 (d, 2H) 7.88 (d, 2H) 7.70 (d, 2H) 5.82 (s, 1H) 7.71 (d, 2H) 7.78 (d, 2H) 7.12 (s, 2H) 4.25 (s, 2H) 7.28 (s, 2H) 7.31 (s, 2H) 6.75 (d, 1H) 3.40 (t, 2H) 6.60 (s, 1H) 6.58 (d, 1H) 4.45 (m, 1H) 2.82 (t, 2H) 3.58 (s, 2H) 3.60 (m, 4H) 2.25 (m, 6H) 2.06 (s, 3H) 2.10 (m, 2H) 1.20 (m, 6H) 1.90 (m, 2H) 1.78 (m, 2H) 1.55 (m, 4H) Yield 16% 7% 61% 35% Melting Point Mass 440 (ES) 480 (ES) 443 (EI) 321 (EI)

Example

No. 190 191* 192* 193 10.61 (s, 1H) 9.67 (s, 1H) 9.63 (s, 1H) 10.61 (s, 1H) 8.28 (s, 1H) 8.08 (s, 1H) 8.06 (s, 1H) 8.28 (s, 1H) 7.82 (d, 2H) 7.88 (d, 2H) 7.85 (d, 2H) 7.78 (m, 4H) 7.73 (d, 2H) 7.65 (d, 2H) 7.65 (d, 2H) 7.45 (d, 1H) 7.53 (br, 1H) 7.11 (s, 2H) 7.15 (s, 2H) 7.20 (s, 2H) 7.25 (s, 2H) 6.35 (d, 1H) 6.55 (d, 1H) 4.30 (br, 2H) 4.25 (m, 1H) 4.10 (m, 1H) 3.95 (m, 1H) 3.53 (m, 2H) 2.59 (br, 1H) 3.62 (m, 4H) 3.58 (m, 4H) 1.21 (d, 3H) 2.21 (br, 1H) 2.45 (m, 4H) 2.50 (m, 4H) 1.94 (m, 1H) 2.19 (m, 4H) 1.96 (m, 1H) 1.40 (m, 7H) 1.88 (m, 4H) 1.50 (m, 4H) 1.65 (m, 4H) 1.30 (m, 4H) Yield 63% 15% 17% 57% Melting Point Mass 437 (EI) 511 (ES) 511 (EI) 403 (EI)

Example

No. 194 195 196 197 9.89 (s, 1H) 10.98 (s, 1H) 10.39 (s, 1H) 10.85 (s, 1H) 8.21 (s, 1H) 8.51 (br, 1H) 8.30 (s, 1H) 8.71 (d, 1H) 7.82 (d, 2H) 8.29 (s, 1H) 8.04 (d, 2H) 8.31 (s, 1H) 7.65 (m, 3H) 7.81 (m, 4H) 7.70 (d, 2H) 7.72 (d, 2H) 7.17 (br, 2H) 7.29 (br, 2H) 7.21 (br, 2H) 7.55 (d, 2H) 4.30 (m, 2H) 3.45 (m, 4H) 6.55 (s, 1H) 7.30 (m, 6H) 1.68 (m, 2H) 3.49 (s, 1H) 5.41 (m, 1H) 1.45 (m, 2H) 2.32 (m, 2H) 3.49 (m, 2H) 1.85 (m, 2H) 2.11 (m, 2H) 1.60 (m, 5H) 1.29 (m, 1H) Yield 26% 56% 12% 61% Melting Point Mass 476 (EI) 417 (EI) 450 (EI) 479 (EI)

Example

No. 198 199 200 201 11.01 (s, 1H) 11.01 (s, 1H) 9.16 (s, 1H) 8.32 (s, 1H) 8.32 (s, 1H) 8.07 (s, 1H) 8.10 (d, 1H) 8.10 (d, 1H) 7.89 (d, 2H) 7.80 (m, 4H) 7.80 (m, 4H) 7.67 (d, 2H) 7.30 (br, 2H) 7.30 (br, 2H) 7.15 (s, 2H) 3.70 (m, 1H) 3.70 (m, 1H) 6.45 (d, 1H) 1.80 (m, 5H) 1.80 (m, 5H) 4.35 (s, 2H) 1.48 (m, 1H) 1.48 (m, 1H) 3.97 (m, 1H) 1.29 (m, 2H) 1.29 (m, 2H) 3.40 (m, 4H) 1.07 (m, 1H) 1.07 (m, 1H) 2.85 (m, 1H) 0.83 (d, 3H) 0.83 (d, 3H) 2.55 (m, 1H) 1.82 (m, 2H) 1.61 (m, 6H) Yield 4% 4% 7% 2% Melting Point Mass 439 (EI) 439 (EI) 515 (ES) 515 (ES)

Example

No. 202 203 * 204 * 205 10.21 (s, 1H) 9.66 (s, 1H) 9.73 (s, 1H) 8.18 (s, 1H) 8.08 (s, 1H) 8.11 (s, 1H) 8.10 (d, 2H) 7.90 (d, 2H) 7.82 (d, 2H) 7.92 (d, 2H) 7.69 (d, 2H) 7.65 (d, 2H) 6.39 (d, 1H) 7.15 (s, 2H) 7.12 (s, 2H) 4.80 (br, 1H) 6.53 (d, 1H) 6.80 (d, 1H) 4.05 (m, 1H) 3.93 (m, 1H) 4.67 (m, 1H) 3.62 (m, 2H) 2.05 (m, 5H) 3.13 (m, 1H) 2.00 (m, 1H) 1.51 (m, 2H) 2.86 (m, 3H) 0.99 (d, 3H) 1.15 (m, 2H) 2.18 (m, 2H) 0.92 (d, 3H) 0.42 (m, 2H) 0.25 (m, 2H) Yield 10% 2% 2% 16% Melting Point Mass 483 (ES) 480 (EI) 480 (EI) 430 (ES)

Example

No. 206 207 208 209 9.75 (s, 1H) 10.98 (s, 1H) 11.00 (s, 1H) 9.55 (s, 1H) 8.19 (s, 1H) 8.50 (d, 2H) 8.31 (s, 1H) 8.08 (s, 1H) 7.75 (d, 2H) 8.31 (s, 1H) 7.74 (m, 5H) 7.80 (d, 2H) 7.18 (d, 2H) 7.97 (d, 2H) 7.21 (d, 1H) 7.60 (d, 2H) 7.17 (s, 2H) 7.78 (d, 2H) 6.80 (d, 1H) 6.58 (br, 4H) 6.68 (d, 1H) 7.57 (d, 1H) 4.00 (m, 1H) 6.20 (d, 1H) 5.35 (t, 1H) 7.00 (t, 1H) 3.62 (m, 2H) 4.80 (br, 1H) 4.71 (m, 1H) 4.01 (m, 1H) 1.95 (m, 1H) 4.04 (m, 1H) 3.91 (m, 2H) 3.62 (m, 2H) 0.98 (d, 3H) 3.60 (m, 2H) 3.65 (s, 3H) 1.97 (m, 1H) 0.90 (d, 3H) 2.00 (m, 1H) 0.98 (d, 3H) 0.99 (d, 3H) 0.92 (d, 3H) 0.92 (d, 3H) Yield 5% 55% 44% 77% Melting 223 248 228 231 Point Mass 446 (ES) 507 (EI) 514 (EI)

Example

No. 210 211 212 71 10.03 (s, 1H) 10.90 (s, 1H) 9.18 (s, 1H) 9.66 (s, 1H) 8.38 (s, 1H) 8.40 (m, 1H) 9.05 (s, 1H) 8.08 (s, 1H) 8.14 (s, 1H) 8.30 (s, 1H) 7.98 (s, 1H) 7.88 (d, 2H) 7.81 (d, 2H) 7.88 (d, 2H) 7.18 (m, 2H) 7.63 (m, 3H) 7.60 (d, 1H) 7.73 (d, 2H) 6.98 (m, 2H) 7.28 (t, 1H) 7.30 (m, 7H) 7.38 (br, 1H) 6.31 (m, 1H) 7.11 (s, 2H) 4.99 (s, 2H) 3.45 (m, 4H) 4.45 (t, 1H) 6.88 (s, 1H) 3.42 (m, 2H) 2.38 (s, 3H) 3.47 (m, 4H) 3.65 (m, 2H) 2.97 (m, 2H) 1.62 (m, 2H) 1.63 (m, 2H) 2.88 (t, 2H) 1.58 (m, 2H) 1.45 (m, 2H) 1.48 (m, 2H) 1.30 (m, 4H) Yield 86% 22% 41% 77% Melting Point Mass 528 (CI) 429 (EI) 352 (EI) 437 (EI)

Example

No. 213 61 214 215 12.40 (br, 1H) 12.41 (br, 1H) 8.03 (s, 1H) 9.55 (s, 1H) 11.10 (s, 1H) 11.11 (s, 1H) 7.76 (m, 4h) 8.10 (s, 1H) 8.08 (d, 2H) 8.10 (d, 1H) 3.70 (s, 2H) 7.80 (d, 2H) 7.79 (m, 4H) 7.80 (m, 5H) 1.92 (m, 4H) 7.68 (d, 2H) 7.30 (s, 2H) 7.30 (s, 2H) 0.92 (m, 6H) 7.15 (s, 2H) 4.04 (m, 1H) 4.08 (m, 1H) (in MeOD) 5.82 (s, 1H) 3.60 (m, 2H) 3.63 (m, 2H) 3.74 (d, 1H) 2.07 (s, 3H) 2.50 (m, 2H) 3.52 (d, 1H) 2.00 (m, 1H) 2.01 (m, 1H) 2.72 (m, 1H) 0.97 (d, 3H) 1.15 (t, 3H) 1.35 (s, 3H) 0.90 (d, 3H) 0.99 (d, 3H) 0.97 (d, 3H) 0.92 (d, 3H) 0.91 (d, 3H) Yield 49% 25% 2% 9% Melting Point Mass 365 (EI) 379 (EI) 443 (ES) 444 (ES)

Example

No. 216 217 218 219 10.88 (s, 1H) 10.88 (s, 1H) 11.01 (s, 1H) 11.11 (s, 1H) 8.36 (s, 1H) 8.36 (s, 1H) 8.52 (br, 1H) 8.53 (m, 1H) 8.03 (d, 1H) 8.03 (d, 1H) 8.29 (s, 1H) 8.36 (s, 1H) 7.79 (m, 4H) 7.79 (m, 4H) 7.78 (m, 4H) 7.80 (m, 4H) 7.28 (br, 2H) 7.28 (br, 2H) 7.32 (s, 2H) 7.31 (s, 2H) 4.65 (m, 1H) 4.65 (m, 1H) 3.39 (m, 2H) 3.71 (m, 2H) 3.89 (m, 2H) 3.89 (m, 2H) 1.70 (m, 6H) 2.65 (m, 2H) 3.71 (m, 2H) 1.15 (m, 3H) 2.19 (m, 2H) 0.96 (m, 2H) Yield 65% 34% 58% 88% Melting 239 239 238 280 Point Mass 439 (EI) 413 (EI) 439 (EI) 416 (EI)

Exam-

ple No. 74 56 220 221 9.67 (s, 1H) 9.70 (s, 1H) 8.92 (m, 1H) 9.66 (s, 1H) 8.11 (s, 1H) 8.81 (m, 1H) 8.08 (s, 1H) 7.88 (m, 4H) 7.96 (s, 1H) 7.83 (d, 2H) 6.25 (d, 1H) 7.43 (d, 2H) 7.68 (d, 2H) 4.81 (m, 1H) 6.67 (d, 2H) 7.22 (t, 1H) 4.05 (m, 1H) 6.20 (m, 1H) 7.11 (s, 2H) 3.61 (m, 2H) 4.38 (m, 1H) 3.95 (m, 4H) 2.01 (m, 1H) 3.48 (m, 1H) 3.48 (m, 2H) 0.97 (d, 3H) 3.37 (m, 1H) 1.79 (m, 4H) 0.92 (d, 3H) 1.20 (d, 3H) 1.18 (t, 6H) Yield 7% 17% 65% 19% Melting 285 158 166 Point Mass 457 (EI) 392 (EI) 354 (EI) 522 (ES)

Exam-

ple No. 222 223 224 225 9.81 (s, 1H) 9.71 (s, 1H) 9.70 (s, 1H) 10.29 (s, 1H) 9.08 (s, 1H) 8.13 (s, 1H) 8.08 (s, 1H) 8.83 (m, 2H) 8.68 (s, 1H) 7.89 (d, 2H) 7.88 (d, 2H) 8.51 (m, 1H) 8.35 (m, 1H) 7.66 (d, 2H) 7.65 (d, 2H) 8.26 (s, 1H) 8.20 (s, 1H) 7.31 (t, 1H) 7.25 (m, 3H) 7.93 (d, 2H) 8.02 (t, 1H) 7.14 (s, 2H) 6.11 (m, 1H) 7.60 (d, 2H) 7.63 (m, 5H) 3.98 (m, 2H) 3.40 (m, 5H) 7.51 (d, 2H) 7.17 (s, 2H) 3.69 (s, 3H) 7.25 (br, 2H) 7.03 (s, 1H) 3.64 (s, 3H) 4.90 (d, 2H) 4.82 (d, 2H) Yield 54% 23% 7% 43 Melting 300 300 243 Point Mass 501 (EI) 465 (EI) 434 (EI)

Exam-

ple No. 226 227 228 229 10.38 (s, 1H) 10.30 (s, 1H) 10.52 (s, 1H) 10.88 (s, 1H) 8.52 (br, 1H) 8.78 (m, 1H) 8.66 (m, 1H) 8.92 (m, 1H) 8.23 (s, 1H) 8.36 (m, 3H) 8.28 (s, 1H) 8.33 (s, 1H) 7.72 (m, 4H) 7.81 (m, 2H) 7.63 (m, 4H) 7.72 (d, 2H) 7.36 (m, 1H) 7.60 (m, 4H) 7.26 (m, 6H) 7.62 (d, 2H) 7.22 (s, 2H) 7.22 (br, 2H) 4.63 (d, 2H) 7.30 (m, 4H) 7.03 (m, 1H) 4.94 (d, 2H) 6.89 (d, 2H) 6.95 (m, 1H) 4.62 (d, 2H) 4.80 (d, 2H) 3.70 (s, 3H) Yield 47% 41% 88% 89% Melting 229 287 259 233 Point Mass 440 (CI) 434 (EI) 451 (EI) 463 (EI)

Example No. 230 10.45 (s, 1H) 8.20 (s, 1H) 3.05 (m, 1H) 7.79 (m, 4H) 7.21 (s, 2H) 3.50 (m, 2H) 1.83 (m, 2H) 1.56 (m, 2H) AusMelting 58% Point >300 Mass 466 (ES)

Exam- ple No. 231 232 233 234 10.3 (s, 1H) 9.28 (s, 1H) 10.48 (s, 1H) 9.63 (s, 1H) 8.34 (tr, 1H) 8.0 (s, 1H) 8.25 (s, 1H) 8.12 (s, 1H) 8.2 (s, 1H) 7.73 (d, 2H) 7.85 (m, 4H) 7.65 (m, 4H) 7.9 (m, 4H) 7.63 (tr, 1H) 7.25 (m, 1H) 7.42 (d, 2H) 4.3 (q, 2H) 7.18 (d, 2H) 7.15 (s, 1H) 7.35 (tr, 2H) 4.2 (m, 2H) 5.0 (m, 1H) 5.1 (m, 1H) 7.21 (m, 1H) 3.23 (tr, 1H) 4.3 (s, 2H) 3.58 (m, 4H) 7.16 (s, 1H) 1.32 (tr, 3H) 4.14 (m, 2H) 5.35 (m, 1H) 3.11 (tr, 1H) 1.55 (d, 3H) Yield 85% 35% 33% 25% Melting Point Mass 330 (EI) 288 (EI) 389 (CI) 448 (ESI)

Exam-

ple No. 235 236 237 238 Point [° C.] Mass 486 (ES) 516 (ES) 504 (ES) 488 (ES)

Exam-

ple No. 239 240 241 242 Point [° C.] Mass 536 (ES) 502 (ES) 484 (ES) 551 (ES)

Exam-

ple No. 243 244 245 Point [° C.] Mass 516 (ES) 514 (ES) 433 (ES)

Exam-

ple No. 246 247 248 249 Point 205 >300 [° C.] Mass 446 (ES) 415 (EI) 504 (ES) 431 (ES)

Exam-

ple No. 250 251 252 253 Point 113 231 187 [° C.] Mass 488 (ES) 446 (ES) 433 (ES)

  

No. 254 255 Melting Point [° C.] Mass 399 (ES) 444 (ES)

No. 256 257 Melting Point [° C.] Mass 474 (ES) 486 (ES)

Compounds Nos. 159, 160, 161, 163, 167, 168, 170, 174, 175, 191, 192, 203 and 204 that are identified with *) can be produced by the process variants that are described under Example No. 295.

EXAMPLE 258 Production of 4-(5-bromo-4-morpholin-4-yl-pyrimidin-2-ylamino)-phenylsulfonamide

202 mg (0.60 mmol) of the compound of Example No. 122 is mixed with 1 ml of water and 0.2 g (1.2 mmol) of bromine and stirred at room temperature. After 24 hours, 0.2 g (1.2 mmol) of bromine is added again, and it is stirred for another 24 hours at room temperature. The solvent is evaporated by means of underpressure, and the remaining residue is purified by chromatography (Flashmaster II, DCM/MeOH 7:3). 17 mg (0.04 mmol, 7%) of the product is obtained as a white solid.

Example

No. 259 260 261 262 Melting 205–207 202–203 Point [° C,] Mass MS (ES) 452, 428 (ES) 454 (M+ H, 100%)

Example No. Compound ESI-MS 263

434 264

434 265

477 266

477 267

552 268

552

Analogously to the process for the production of the intermediate products described under Example 6.0 (see Production of Intermediate Products, page 186), the following compounds are also produced:

Example 269 270 271 No.

Yield 47% 90% Mass ESI: ESI: ESI: MH⁺ 480 MH⁺ 432 MH⁺ 446 (18%) (100%) (100%) 478 (97%) 430 (94%) 115 (30%) 157 (43%)

Analogously to production example 1, the following compounds are also produced:

Example 272 273 No. Yield 61% 44% Mass EI: EI: M⁺ 463 (4%) M⁺ 403 (24%) 277 (8%) 358 (100%) 105 (100%) 277 (52%)

Example 276 277 No. Yield 81% 58% Mass EI: ESI: M⁺ 431 (5%) MH⁺ 444 372 (100%) (100%) 291 (46%) 442 (97%) 115 (20%)

Example 280 281 No. Yield 55% 43% Mass ESI: ESI: MH⁺ 444 MH⁺ 446 (100%) (100%) 442 (97%) 444 (95%) 214 (12%) 346 (5%)

Example 284 285 No. Yield 51% 46% Mass ESI: ESI: MH⁺ 520 MH⁺ 520 (100%) (100%) 518 (97%) 518 (97%) 115 (27%) 115 (23%)

Example 274 275 No. Yield 42% 68% Mass ESI: EI: MH⁺ 418 M⁺ 401 (33%) 100% 372 (100%) 416 (94%) 344 (38%) 346 (8%)

Example 278 279 No. Yield ~20% 30% Mass ESI: ESI: MH⁺ 494 MH+ 418 (75%) 100%) 346 (18%) 416 (97%) 214 (55%) 310 (27%)

Example 282 283 No. Yield ~18% 35% Mass ESI: ESI: MH⁺ 416 MH⁺ 446 (100%) (100%) 414 (96%) 444 (90%) 317 (4%)

Exmaple 286 287 No. Yield 47% 61% Mass ESI: ESI: MH⁺ 432 MH⁺ 446 (100%) (100%) 430 (95%) 444 (93%) 346 (5%) 115 (31%)

According to the production variants below, the following compounds are also synthesized:

30 mg (0.0678 mmol) of compound No. 277 is dissolved in 1 ml of methanol/tetrahydrofuran 1:1. After the addition of ˜10 mg of sodium borohydride, stirring is continued for 2 hours. Then, it is quenched with ≈3-4 drops of glacial acetic acid while being cooled, and it is concentrated by evaporation. Below, the crude product is taken up with a little water, suctioned off, rewashed with acetonitrile and dried in a vacuum at 60° C. Yield: 21 mg (70% of theory) of the desired compound.

Example 288 289 No. Yield 52% 70% Mass EI: ESI: M⁺ 465 (5%) MH⁺ 446 358 (40%) (100%) 207 (31%) 444 (93%) 117 (20%)

EXAMPLE 290 Production of the Oxime Ether-Pyrimidine Compounds of General Formula I

The production of the oxime ether is carried out according to the following general reaction diagram:

R⁸ and R⁹ have the meanings that are indicated in general formula I.

Production of Example 290

50 mg (0.12 mmol) of compound No. 282, 34 mg of hydroxylammonium chloride and 150 mg of pulverized KOH are refluxed for 2 hours in 2 ml of ethanol. Then, it is poured onto ice water and acidified with glacial acetic acid, extracted 3 times with dichloromethane/isopropanol 4:1, dried with magnesium sulfate and concentrated by evaporation. The residue is suspended with acetonitrile, suctioned off and dried at 60° C.

Yield: 28 mg (54% of theory) of the desired compound.

Mass

ESI:

MH⁺ 429 (29%)

371 (61%)

289 (91%)

Similarly produced are also the following compounds:

Example No. 291 292 293 34% 36% 40% Mass ESI: ESI: ESI: MH+ 443 (95%) MH+ 485 (92%) MH⁺ 487 (91%) 445 (99%) 487 (99%) 489 (89%) 373 (32%) 373 (32%)

EXAMPLE 294 Reductive Amination

50 mg (0.12 mmol) of compound No. 282 and 7.5 mg (0.132 mmol) of cyclopropylamine are dissolved in 2 ml of 1,2-dichloroethane. After 9.1 mg (0.144 mmol) of sodium cyanoborohydride is added, it is allowed to stir for 12 more hours. Then, it is diluted with dichloromethane/isopropanol 4:1, washed 2× with water, dried with magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with dichloromethane/methanol 95:5. Yield: 18 mg (33% of theory) of the desired compound.

Yield 33% Mass ESI: MH⁺ 457 (98%) 455 (93%) 249 (55%)

Produced similarly are also compounds Nos. 159, 160, 161, 163, 167, 168, 170, 174, 175, 191, 192, 203 and 204.

EXAMPLES 295 AND 296

Produced similarly to Example 1 are also the following two compounds:

Example 295 296 Yield 46% 47% Mass ESI: ESI: MH⁺ 432 (30%) MH⁺ 446 (45%) 434 (31%) 448 (49%) 123 (100%) 123 (90%)

Production of the Sulfonamides of General Formula I

0.2 mmol of sulfonic acid fluoride is introduced into the reactor of a synthesizer.

1.0 ml of solvent, preferably 2-butanol, is added. 0.2 ml (0.2 mmol) of DMAP—dissolved in a solvent, for example DMSO or 2-butanol—and 0.2 ml (0.2 mmol) of the amine, dissolved in 2-butanol, are added in succession via a pipette. The reaction mixture is then stirred for 20 hours at 80° C. After the reaction is completed, the crude product is pipetted off, and the reactor is rewashed with 1.0 ml of TMF. The solution of the crude product is then concentrated by evaporation and purified by HPLC.

The following compounds were produced:

Example Molecular No. Compound weight ESI-MS 297

526.4968 526/528 298

562.5298 562/564 299

624.6006 624/626 300

501.4471 501/503 301

538.4682 538/540 302

588.4465 588/590 303

528.5126 528/530 304

542.5394 542/544 305

556.5662 556/558 306

570.593 570/572 307

510.4106 510/512 308

588.4465 588/590 309

548.503 548/550 310

555.4949 555/557 311

500.459 500/502 312

514.4858 514/516 313

515.4739 515/517 314

557.5543 557/559 315

470.3896 470/472 316

551.5069 551/553 317

534.4762 534/536 318

568.9213 568/570 319

524.4374 524/526 320

534.4839 543/545 321

488.4044 488/490 322

526.4776 526/528 323

564.502 564/566 324

527.4849 527/529 325

541.5117 541/543 326

538.4395 538/540 327

541.5117 541/543 328

521.4375 521/523 329

538.4395 538/540 330

521.4375 521/523 331

550.4752 550/552 332

550.4752 550/552 333

613.5551 613/615 334

534.4762 534/536 335

512.47 512/514 336

548.503 548/550 337

610.5738 610/612 338

487.4203 487/489 339

524.4414 524/526 340

574.4197 574/576 341

514.4858 516/514 342

528.5126 528/530 343

542.5394 542/544 344

556.5662 556/558 345

496.3838 496/498 346

574.4197 574/576 347

534.4762 534/536 348

541.4681 541/543 349

486.4322 486/488 350

500.459 500/502 351

501.4471 501/503 352

543.5275 543/545 353

456.3628 456/458 354

537.4801 537/539 355

520.4494 520/522 356

554.8945 554/556 357

510.4106 510/512 358

529.4571 529/531 359

474.3776 474/476 360

512.4508 541/514 361

550.4752 550/552 362

513.4581 513/515 363

527.4849 527/529 364

524.4127 524/526 365

527.4849 527/529 366

507.4107 507/509 367

524.4127 524/526 368

507.4107 507/509 369

536.4484 536/538 370

536.4484 536/538 371

599.5283 599/601 372

520.4494 520/522 373

512.47 512/514 374

548.503 548/550 375

610.5738 610/612 376

524.4414 524/526 377

574.4197 574/576 378

514.4858 514/516 379

528.5126 528/530 380

542.5394 542/544 381

496.3838 496/498 382

574.4197 574/576 383

534.4762 534/536 384

541.4681 541/543 385

486.4322 486/488 386

500.459 500/502 387

501.4471 501/503 388

543.5275 543/545 389

537.4801 537/539 390

520.4494 520/522 391

554.8945 554/556 392

510.4106 510/512 393

529.4571 529/531 394

474.3776 474/476 395

512.4508 512/514 396

513.4581 513/515 397

527.4849 527/529 398

524.4127 524/526 399

527.4849 527/529 400

507.4107 507/509 401

524.4127 524/526 402

507.4107 507/509 403

536.4484 526/538 404

536.4484 536/538 405

599.5283 599/601 406

520.4494 520/522 407

529.4419 529/531 408

534.4762 534/536 409

596.547 596/598 410

473.3935 473/475 411

510.4146 510/512 412

560.3929 560/562 413

500.549 500/502 414

514.4858 514/516 415

528.5126 528/530 416

482.357 482/484 417

560.3929 560/562 418

520.4494 520/522 419

527.4413 527/529 420

472.4054 472/474 421

486.4322 486/488 422

487.4203 487/489 423

529.5007 529/531 424

523.4532 523/525 425

506.4226 506/508 426

540.8677 540/542 427

496.3838 496/498 428

515.4303 515/517 429

460.3508 460/462 430

498.424 498/500 431

499.4313 499/501 432

513.4581 513/515 433

510.3859 510/512 434

513.4581 513/515 435

493.3839 493/495 436

510.3859 510/512 437

493.3839 493/495 438

522.4216 522/524 439

522.4216 522/524 440

585.5015 585/587 441

506.4226 506/508 442

515.4151 515/517 443*)

416.30 416/418 *) is produced according to the process that is described under Sulfonamides

Production of the Pyrimidine-Sulfonyl Fluorides of General Formula I

The production of the pyrimidine-sulfonic acid fluorides is carried out analogously to the production of the sulfonic acid amides.

Melting Point Molecular [° C.] Example No. Compound Weight and ESI-MS 444

405.25 217-220405/407 445

419.27 196-202419/421 446

419.27 165-196419/421 447

433.30 198-204433/435 448

433.30 144-149433/435 449

447.33 219-222447/449

Melting Point Example Molecular [° C.] and No. Compound Weight ESI-MS 450

405.25 170-173405/407 451

419.27 226-228419/421 452

433.30 433/435 453

447.33 447/449 454

433.30 433/435 455

419.27 419/421

The following para compounds are also produced similarly to the above-described examples:

Molecular Example No. Compound Weight ESI-MS 456

498.4432 498/500 457

534.4762 534/536 458

596.547 596/598 459

473.3935 473/475 460

510.4146 510/512 461

560.3929 560/562 462

500.459 500/502 463

514.4858 514/516 464

528.5126 528/530 465

542.5394 542/544 466

560.3929 560/562 467

520.4494 520/522 468

527.4413 527/529 469

472.4054 472/474 470

486.4322 486/488 471

529.5007 529/531 472

442.336 442/444 473

523.4532 523/525 474

506.4226 506/508 475

540.8677 540/542 476

496.3838 496/498 477

515.4303 515/517 478

460.3508 460/462 479

498.424 498/500 480

536.4484 536/538 481

499.4313 499/501 482

513.4581 513/515 483

510.3859 510/512 484

513.4581 513/515 485

493.3839 493/495 486

510.3859 510/512 487

493.3839 493/495 488

522.4216 522/524 489

522.4216 522/524 490

585.5015 585/587 491

506.4226 506/508 492

515.4151 515/517 493

512.47 494

548.503 495

610.5738 496

487.4203 497

524.4414 498

574.4197 499

514.4858 500

528.5126 501

542.5394 502

556.5662 503

496.3838 504

574.4197 505

534.4762 506

541.4681 507

486.4322 508

500.459 509

501.4471 510

543.5275 511

456.3628 512

537.4801 513

520.4494 514

566.4742 515

554.8945 516

510.4106 517

529.4571 518

474.3776 519

512.4508 520

550.4752 521

513.4581 522

527.4849 523

524.4127 524

527.4849 525

507.4107 526

524.4127 527

507.4107 528

536.4484 529

536.4484 530

599.5283 531

520.4494 532

529.4419

Separation of Diastereomer Mixtures of the Compounds According to the Invention Separation in the Example of the Diastereomer Mixture of Compound No. 274

The diastereomer mixture is separated into the two corresponding racemates (A and B) by means of HPLC. Conditions:

Column: Kromasil C18 (5 μm) 150 × 4.6 mm Eluant: 25% acetonitrile/water with 1 ml of NH3/1; Flow: 1.0 ml/min Detection: PDA 300 nm Retention times: Racemate A - 11.6 minutes Racemate B - 12.4 minutes

NMR DMSO-d6: DMSO-d6: 9.68, s, 1 H 9.68, s, 1 H 8.12, s, 1 H 8.11, s, 1 H 7.87, d, 2 H 7.85, d, 2 H 7.70, d, 2 H 7.69, d, 2 H 7.14, s, 2 H 7.16, s, 2 H 6.15, d, 1 H 6.35, d, 1 H 5.01, d, 1 H 4.90, d, 1 H 4.10, m, 1 H 4.08, m, 1 H 3.80, m, 1 H 3.80, m, 1 H 1.22, d, 3 H 1.18, d, 3 H 1.1, d, 3 H 1.12, d, 3 H

Below, racemates A and B in each case are separated by means of chiral HPLC.

Conditions:

Column: Chiralpak AD (10 μm) 250 × 4.6 mm Eluant: Hexane/ethanol 80:20 Flow: 1.0 ml/min Detection: PDA 300 nm Retention times: Enantiomer A1 - 16.6 minutes Enantiomer A2 - 19.6 minutes Enantiomer B1 - 16.0 minutes Enantiomer B2 - 17.8 minutes

Production of the intermediate stages preferably used for the synthesis of the compounds of general formula I according to the invention.

EXAMPLE 1.0 Production of N-(2-chloro-5-fluoro-4-pyrimidinyl)-N-2-propynylamine

11.1 g (66 mmol) of 2,4-dichloro-5-fluoropyrimidine is dissolved in 60 ml of acetonitrile, and 10.2 ml (73 mmol) of triethylamine and 6.0 ml (86 mmol) of propynylamine are added. The reaction mixture is stirred overnight at room temperature and then poured into water. The mixture is extracted by means of ethyl acetate, the combined organic phases are dried on MgSO₂, and the solvent is evaporated by means of underpressure. After the remaining material is recrystallized with diisopropyl ether/hexane, the yield is 10.6 g (87% of theory) of the product.

5-H 8.18 (3.3 Hz, 1H) Solvent: DMSO 4CH 4.14 (dd, 2H) Yield: 87% 3.20 (t, 1H) Melting point: 96° C. NH 8.65 (tb, 1H)

The 4-(diaminocyclohexyl) derivatives that are described below are synthesized via reductive aminations of the described keto derivative with use of triacetoxy borohydride (Abdel-Magid, Carson, Harris, Maryanoff, Sha, J. Org. Chem. 1996, 61, 3849). The keto derivative is obtained by TPAP oxidation (Griffith, Ley, Aldrichimica Acta 1990, 23, 13) of the corresponding alcohol.

Similarly produced are also the following intermediate compounds:

Example No. 1.1 1.2 1.3 1.4 Solvent CDCl₃ DMSO DMSO DMSO 5-H 7.87 (s, 1H) 8.34 (s, 1H) 8.24 (s, 1H) 8.23 (s, 1H) 4CH 4.32 (dd, 2H) 4.48 (q, 1H) 3.59 (td, 2H) 3.21 (t, 2H) 2.30 (t, 1H) 1.93 (dq, 2H) 2.78 (t, 2H) 1.10 (mc, 1H) 0.92 (t, 3H) 7.57 (s, 1H) 0.42 (mc, 2H) 5CH 2.03 (s, 3H) 3.66 (s, 3H) 6.85 (s, 1H) 0.37 (mc, 2H) 7.90 (tb, 1H) 7.84 (t, 1H) NH 4.91 (sb, 1H) 7.69 (d, 1H) 11.92 (sb, 1H) Yield 80% 42% 33% 74% Melting 121-121.5° C. 73° C. 90° C. 98° C. Point

Example No. 1.5 1.6 1.7 1.8 Solvent DMSO DMSO DMSO DMSO 6-H 8.26 (s, 1H) 8.26 (s, 1H) 8.27 (s, 1H) 8.37 (s, 1H) 4CH 3.59 (mc, 2H) 3.58 (mc, 2H) 3.58 (sb, 4H) 4.40 (m, 1H) 3.90 (mc, 1H) 3.97 (mc, 1H) 4.14 (mc, 1H) 3.49 (dd, 1H) 1.98 (mc, 1H) 1.96 (mc, 1H) 3.33 (dd, 1H) 0.94 (d, 3H) 0.92 (d, 3H) 3.26 (s, 3H) 0.86 (d, 3H) 0.84 (d, 3H) 1.15 (d, 3H) OH 4.67 (mb, 1H) 4.74 (t, 1H) 4.78 (sb, 2H) NH 6.75 (sb, 1H) 6.87 (d, 1H) 6.73 (sb, 1H) 7.29 (d, 1H) Yield 82% 91% 41% 74% Melting 113-114° C. 121-122° C. 155-156° C. Öl Point

Example No. 1.9 1.10 Solvent DMSO DMSO 6-H 8.24 (s, 1H) 8.36 (s, 1H) 4CH 3.49 (q, 2H) 4.14 (d, 2H) 2.50 (t, 2H) 3.18 (t, 1H) 2.42 (t, 4H) 3.56 (t, 4H) OH NH 7.57 (sb, 1H) 8.40 (s, 1H) Yeild 31% 73 Melting 118-119° C. 103-104° C. Point

Example No. 1.11 1.12 1.13 1.14 Solvent DMSO DMSO DMSO DMSO 6-H 8.30 (s, 1H) 8.32 (s, 1H) 8.29 (s, 1H) 8.24 (s, 1H) 4.46 (dq, 1H) 5.04 (q, 1H) 3.7-3.9 (2H) 4.25 (m, 1H) 1.38 (d, 3H) 2.39 (m, 2H) 5.19 (m, 1H) 3.48 (m, 2H) 7.2-7.4 (5H) NH 7.60 (sb, 1H) 4.31 (q, 1H) 7.72 (d, 1H) 1.86 (m, 2H) 5.09 (t, 1H) OH 7.29 (sb, 1H) 4.40 (t, 1H) 2.43 (m, 2H) 7.21 (d, 1H) 8.13 (d, 1H) 2.03 (s, 3H) 7.13 (d, 1H) 4.88 (t, 1H) Yeild 87% 63% 99% 78% Melting 234° C. Zers. 210° C. Zers. 152-153° C. 130° C. Point

Example No. 1.15 1.16 1.17 Solvent DMSO DMSO DMSO 6-H 8.20 (s, 1H) 8.21 (s, 1H) 8.22 (s, 1H) 3.55 (m, 2H) 3.33 (q, 2H) 3.39 (q, 2H) 4.22 (m, 1H) 1.53 (m, 4H) 2.26 (t, 2H) 5.03 (m, 2H) 1.28 (m, 2H) 1.79 (q, 2H) 7.1–7.4 (5H) 2.29 (t, 2H) NH 6.53 (d, 1H) 7.74 (t, 1H) 7.78 (t, 1H) 5.93 (d, 1H) 12.11 (sb, 1H) Yeild 93% 99% 11% Melting Öl Öl Öl Point

Example No. 1.18 1.19 1.20 Yield 86% 64% 87% Mass ESI: ESI: Cl: MH⁺ 297 (2%) MH⁺ 311 (2%) M+ 354 (100%) 266 (22%) 248 (20%) 352 (72%) 234 (30%) 236 (18%) 308 (54%)

Example No. 1.21 1.22 1.23 Yeild 26% ~20% 89% Mass EI: NMR, CDCl3 EI: M⁺ 327 (10%) 8.16 (s, 1H) M⁺ 265 (15%) 222 (36%) 6.55 (s, 1H) 236 (100%) 105 (100%) 4.43 (d, 2H) 209 (18%) 1.29 (s, 9H)

Example No. 1.24 1.25 1.26 Yeild 75% 70% 83% Mass Cl: Cl ESI: M⁺ 384 M⁺ 384 (100%) 319 3% (100%) 212 (21%) 278 100% 212 (21%) 91 (7%) 220 68% 91 (7%)

Example No. 1.27 Yeild 98% Mass ESI: MH⁺296 (90%) 298 (100%) 210 (12%)

EXAMPLE 2.0 Production of 5-Bromo-2-chloro-4-(4,4,4-trifluorobutoxy)pyrimidine

3.19 g (14 mmol) of 5-bromo-2,4-dichloropyrimidine is mixed with 8.06 g (63 mmol) of 4,4,4-trifluorobutanol, and 0.74 ml (8.4 mmol) of trifluoromethanesulfonic acid is slowly added to it. The reaction mixture is stirred overnight at room temperature and then poured into water. The mixture is extracted by means of ethyl acetate, the combined organic phases are dried on MgSO₂, and the solvent is evaporated by means of underpressure. The product is always contaminated with varying amounts of 2,4-bisalkoxypyrimidine. The remaining material is therefore purified by means of gradient chromatography with silica gel as a carrier medium (eluant: hexane and hexane/ethyl acetate at a 9:1 ratio). This process results in a yield of 1.70 g (38%) and also yields 1.93 g (34%) of 5-bromo-2,4-bis-(4,4,4-trifluorobutoxy)pyrimidine (starting compound).

5-H4CH5CH- 8.74(s, 1H) Chromatography: H to H/EA 9:14.48(t, 2H) Yield: 38%2.00(mc, 2H)Melting point: 66.5-67.5°2.44(mc, 2H)

Similarly produced are also the following compounds:

Example No. 2.1 2.2 CDCl₃ DMSO 5-H 8.49(s, 1H) 8.75(s, 1H) 4CH 5.10(d, 2H) 4.05(mc, 2H) 3.79(mc, 2H) 3.60(mc, 2H) 5CH 2.59(t, 1H) 3.48(mc, 2H) 3.40(t, 2H) 1.07(t, 3H) Chrom. H to DCM to DCM/ H/EA 4:1 MeOH 95:5 Yield 78% 11% Melting 55° C. Oil Point

Analogously to process examples 1 and 2, the following intermediate products are also produced:

Example No. 1-2.1 1-2.2 Solvent DMSO DMSO 8.26(s, 1H) 8.26(s, 1H) 6.65(d, 1H) 6.65(d, 1H) 4.70(t, 1H) 4.70(t, 1H) 4.10(dt, 1H) 4.10(dt, 1H) 3.65(at, 2H) 3.65(at, 2H) 0.90(s, 9H) 0.90(s, 9H) Yield 49% 70% Mass 309(EI) 309(EI)

Example No. 1-2.5 1-2.6 Solvent DMSO DM30 8.15(s, 1H) 8.22(s, 1H) 7.25(t, 1H) 4.82(t, 1H) 3.16(s, 2H) 4.49(br, 1H) 1.90(s, 3H) 3.85(m, 1H) 1.61(q, 6H) 3.76(m, 1H) 1.41(s, 6H) 3.54(m, 1H) 3.40(m, 1H) 1.93(m, 3H) 1.80(m, 1H) Yield 70% 75% Mass 357(EI) 293(EI)

Example No. 1-2.9 1-2.10 Solvent DMSO DMSO 8.38(s, 1H) 8.22(s, 1H) 4.81(br, 1H) 7.05(d, 1H) 3.96(m, 2H) 4.82(t, 1H) 3.72(m, 1H) 4.18(m, 1H) 3.30(m, 2H) 3.42(m, 2H) 1.81(m, 2H) 1.15(d, 3H) 1.48(m, 2H) Yield 19% 71% Mass 292(EI) 266(EI)

Example No. 1-2.13 1-2.14 Solvent DMSO DMSO 8.41(s, 1H) 8.25(s, 1H) 8.11(s, 1H) 4.53(m, 1H) 4.28(t, 2H) 3.88(m, 2H) 3.70(dd, 1H) 3.62(dd, 1H) 2.16(m, 1H) 2.02(m, 1H) 7.56(d, 1H) Yield 46% 72% Mass 390(FAB) 277(EI)

Example No. 1-2.17 1-2.18 Solvent DMSO DMSO 8.21(s, 1H) 8.35(t, 1H) 7.22(d, 1H) 8.19(s, 1H) 3.88(m, 1H) 3.40(m, 2H) 1.70(m, 4H) 2.97(p, 1H) 1.50(m, 2H) 2.22(m, 4H) 1.28(m, 1H) 2.08(dd, 1H) 1.01(m, 2H) 1.70(m, 6H) 0.82(d, 3H) Yield 22% 32% Mass 303(EI) 320(EI)

Example No. 1-2.21 1-2.22 Solvent DMSO DM30 8.25(s, 1H) 8.25(s, 1H) 8.08(d, 1H) 7.38(d, 1H) 7.35(m, 5H) 4.44(m, 1H) 5.30(m, 1H) 2.60(m, 2H) 4.81(t, 1H) 2.24(m, 2H) 3.45(m, 2H) 2.07(m, 2H) 2.05(m, 2H) 1.90(m, 2H) Yield 97% 58% Mass 343(EI) 304(ES)

Example No. 1-2.25 1-2.26 Solvent DMSO DMSO 8.22(s, 1H) 7.21(d, 1H) 3.82(m, 1H) 2.45(m, 4H) 2.22(m, 1H) 1.78(m, 8H) 1.45(m, 6H) Yield n.b. 26% Mass 344(EI) 374(EI)

Example No. 1-2.29 1-2.30 Solvent DMSO DMSO 8.22(s, 2H) 8.21(s, 1H) 7.28(d, 1H) 7.18(d, 1H) 7.10(d, 1H) 4.62(s, 1H) 4.00(m, 1H) 4.20(m, 1H) 3.85(m, 1H) 3.95(m, 1H) 2.19(s, 6H) 2.75(dd, 1H) 2.17(s, 6H) 2.50(m, 2H) 2.15(m, 1H) 2.31(dd, 1H) 2.00(m, 1H) 2.15(s, 1H) 1.82(m, 8H) 2.00(m, 1H) 1.50(m, 6H) 1.82(m, 4H) 1.25(m, 2H) 1.55(m, 5H) Yield 13% 35% Mass 334(EI) 374(EI)   

Example No. 1-2.33 1-2.34 Solvent DMSO CDCl3 8.50(s, 1H) 8.08(s, 1H) 4.10(m, 2H) 6.04(m, 1H) 3.72(m, 1H) 5.71(br, 1H) 3.30(m, 2H) 4.48(d, 2H) 1.75(m, 2H) 3.71(s, 3H) 1.35(m, 2H) 2.25(s, 3H) Yield 3% 30% Mass 291(EI) 300(ES)

Example No. 1-2.37 1-2.38 Solvent CDCl3 CDCl3 8.14(s, 1H) 8.20(s, 1H) 5.41(m, 1H) 7.71(m, 1H) 4.49(m, 1H) 7.30(m, 6H) 2.44(m, 6H) 4.97(s, 2H) 1.79(m, 2H) 3.00(m, 2H) 1.40(m, 8H) Yield 58% 77% beute Mass 304(ES) 427(ES)

Example No. 1-2.41 1-2.42 Solvent DMSO DMSO 8.19(s, 1H) 8.21(s, 1H) 7.21(d, 1H) 7.03(d, 1H) 4.03(m, 1H) 4.83(t, 1H) 1.60(m, 12H) 4.13(m, 1H) 3.47(m, 2H) 1.12(d, 3H) Yield 73% 61% Mass 303(EI) 267(EI)

Example No. 1-2.45 1-2.46 Solvent DMSO DMSO 8.36(s, 1H) 8.26(s, 1H) 6.56(s, 1H) 8.06(d, 1H) 3.81(s, 1H) 7.30(m, 5H) 2.28(m, 2H) 5.29(m, 1H) 1.83(m, 2H) 4.81(t, 1H) 1.58(m, 6H) 3.42(m, 2H) 2.10(m, 2H) Yield 84% 97% Mass 314(EI) 343(EI)

Example No. 1-2.49 1-2.50 Solvent DMSO DMSO 8.29(s, 1H) 8.18(s, 1H) 6.05(s, 1H) 7.25(d, 1H) 5.18(m, 1H) 4.15(m, 1H) 3.54(s, 2H) 2.40(m, 6H) 1.92(m, 2H) 1.50(m, 4H) 1.76(m, 2H) 1.17(d, 3H) 0.90(dd, 6H) Yield 16%. 52% Mass 308(EI) 350(EI)

Example No. 1-2.53 1-2.54 Solvent DMSO DMSO 8.22(s, 1H) 7.75(s, 1H) 7.65(t, 1H) 6.55(d, 1H) 7.30(m, 6H) 4.54(m, 1 5.01(s, 2H) 3.38(m, 2H) 3.04(m, 2H) 1.68(m, 2H) Yield 77% 50% Mass 398(EI) 229(EI)

Exam- ple No. 1-2.3 1-2.4 Solvent DMSO DMSO 8.29(s, 1H) 8.28(s, 1H) 6.32(s, 1H) 7.09(d, 1H) 4.89(t, 3H) 5.05(d, 1H) 3.74(d, 6H) 3.95(m, 1H) 3.60(m, 5H) 1.30(s, 3H) 1.28(s, 3H) Yield 16% 92% Mass 314(EI) 354(EI)

Exam- ple No. 1-2.7 1-2.8 Solvent DMSO DMSO 8.28(s, 1H) 8.22(s, 1H) 6.29(s, 1H) 7.23(d, 1H) 5.31(t, 1H) 4.60(d, 1H) 3.39(d, 2H) 3.85(m, 1H) 1.39(s, 6H) 3.35(m, 1H) 1.80(m, 4H) 1.53(m, 2H) 1.20(m, 2H) Yield 46% 24% Mass 281(EI) 305(EI)

Exam- ple No. 1-2.11 1-2.12 DMSO DMSO 8.21(s, 1H) 8.31(s, 1H) 7.06(d, 1H) 7.32(d, 1H) 4.81(t, 1H) 4.35(s, 1H) 4.22(m, 1H) 3.68(s, 3H) 3.47(m, 2H) 2.32(m, 1H) 1.51(m, 2H) 0.90(dd, 6H) 1.37(m, 1H) 0.88(m, 6H) Yield 99% 77% Mass 308(EI) 322(ES)

Exam- ple No. 1-2.15 1-2.16 Solvent DMSO DMSO 8.19(s, 1H) 8.19(s, 1H) 7.65(t, 1H) 7.30(d, 1H) 3.18(t, 2H) 3.65(m, 1H) 1.62(m, 6H) 1.68(m, 5H) 1.16(m, 3H) 1.25(m, 4H) 0.90(m, 2H) 0.78(d, 3H) Yield 68% 31% Mass 303(EI) 305(EI)

Exam- ple No. 1-2.19 1-2.20 Solvent DMSO DMSO 8.21(s, 1H) 8.20(s, 1H) 7.81(t, 1H) 7.71(t, 1H) 3.41(dd, 2H) 4.45(br, 1H) 2.31(m, 10H) 3.40(m, 4H) 2.13(s, 3H) 1.60(m, 2H) 1.70(p, 2H) 1.44(m, 2H) Yield 28% 98% Mass 349(EI) 281(EI)

Exam- ple No. 1-2.23 1-2.24 Solvent DMSO DMSO 8.20(s, 1H) 8.21(s, 1H) 7.28(d, 1H) 7.24(d, 1H) 4.19(m, 1H) 7.02(t, 1H) 2.40(m, 6H) 4.40(m, 1H) 1.50(m, 4H) 3.92(m, 1H) 1.15(d, 3H) 2.95(q, 2H) 0.91(t, 6H) 1.95(m, 2H) 1.82(m, 2H) 1.59(m, 2H) 1.3(m, 6H) 0.82(t, 3H) Yield 52% 70% Mass 348(EI)

Exam- ple No. 1-2.27 1-2.28 Solvent DMSO DMSO 8.25(s, 1H) 8.22(s, 1H) 6.87(d, 1H) 7.28(d, 1H) 4.02(m, 1H) 3.85(m, 1H) 2.45(m, 4H) 2.19(s, 6H) 2.22(m, 1H) 2.15(m, 1H) 1.78(m, 8H) 1.82(m, 4H) 1.45(m, 6H) 1.50(m, 2H) 1.25(m, 2H) Yield 23% 51% Mass 374(EI) 334(EI)

Exam- ple No. 1-2.31 1-2.32 Solvent DMSO DMSO 8.21(s, 1H) 8.71(s, 1H) 7.22(d, 1H) 5.32(m, 1H) 4.65(s, 1H) 3.82(m, 2H) 4.15(m, 1H) 3.55(m, 2H) 3.85(m, 1H) 2.00(m, 2H) 2.78(m, 1H) 1.70(m, 2H) 2.60(m, 1H) 2.38(dd, 1H) 1.95(m, 3H) 1.80(m, 2H) 1.52(m, 3H) 1.20(m, 2H) Yield 21% 40% Mass 374(EI) 292(EI)

Exam- ple No. 1-2.35 1-2.36 Solvent DMSO CDCl3 8.23(s, 1H) 8.11(s, 2H, 1+2) 7.27(d, 1H) 5.55(m, 1H, 1) 7.04(t, 1H) 5.29(m, 1H, 2) 4.46(m, 1H) 4.25(m, 1H, 1) 3.95(m, 1H) 3.98(m, 1H, 2) 2.94(m, 2H) 3.72(m, 8H, 1+2) 1.92(m, 4H) 2.65(m, 8H, 1+2) 1.62(m, 2H) 1.70 1.32(m, 6H) (m, 18H, 1+2) 0.84(t, 3H) Yield 70% 66% Mass 405(ES) 375(ES)

Exam- ple No. 1-2.39 1-2.40 Solvent DMSO DMSO 8.22(s, 1H) 8.22(s, 1H) 6.35(s, 1H) 7.12(d, 1H) 5.19(t, 1H) 4.10(m, 1H) 3.54(d, 2H) 2.20(m, 1H) 2.00(m, 2H) 1.89(m, 1H) 1.75(m, 4H) 1.35(m, 8H) 1.53(m, 2H) Yield 48% 60% Mass 308(EI) 301(EI)

Exam- ple No. 1-2.43 1-2.44 Solvent DMSO DMSO 8.28(s, 1H) 8.41(s, 1H) 3.62(q, 4H) 8.15(t, 1H) 1.18(t, 6H) 4.21(td, 2H) Yield 13% 21% Mass 265(EI) 339(EI)

Exam- ple No. 1-2.47 1-2.48 Solvent DMSO DMSO 8.32(t, 1H) 8.15(s, 1H) 8.15(s, 1H) 7.06(d, 1H) 3.40(m, 2H) 4.65(br, 1H) 2.34(m, 2H) 3.79(m, 1H) 2.18(s, 6H) 3.52(m, 1H) 1.69(m, 2H) 1.86(m, 2H) 1.61(m, 2H) 1.25(m, 4H) Yield 22% 53% Mass 294(EI) 307(EI)

Exam- ple No. 1-2.51 1-2.52 Solvent DMSO DMSO 8.29(s, 1H) 8.38(s, 1H) 6.18(s, 1H) 7.28(d, 1H) 5.15(t, 1H) 5.28(t, 1H) 3.70(m, 1H) 4.65(m, 1H) 3.49(m, 1H) 3.86(m, 2H) 2.60(m, 1H) 3.65(s, 3H) 0.92(d, 3H) 0.83(d, 3H) Yield 27% 63% Mass 308(EI) 309(EI)

Exam- ple No. 1-2.55 Solvent DMSO 8.18(s, 1H) 7.69(t, 1H) 4.32(br, 1H) 3.35(m, 4H) 1.40(m, 6H) Yield 43% Mass 295(EI)

EXAMPLE 3.0 Production of Amines

4.5 g (20 mmol) of 2-bromobutyraldehyde diethyl acetyl (Pfaltz-Bauer Company) and 5.2 g (80 mmol) of sodium azide are stirred for 5 days in 15 ml of DMF at 100° C. Then, it is poured onto cold dilute sodium bicarbonate solution, and extracted 3× with ether. The organic phase is dried with magnesium sulfate and concentrated by evaporation: raw yield 1.87 g (50% of theory).

936 mg of the crude product is dissolved in 50 ml of methanol, mixed with palladium on carbon (10%) and stirred for 12 hours under H₂ atmosphere. After the catalyst is filtered off and after concentration by evaporation, 457 mg (57% of theory) of the desired amine remains.

Example No. 3.0 3.1 3.2 3.3 Yield 50% 57% 50% 71% NMR 4,38(d, 1H) 4,19(d, 1H) 4, 38(d, 1H) 4,25(d, 1H) CDCl3 3,72(m, 2H) 3,68(m, 2H) 3,58(m, 2H) 3,5(m, 1H) 3,6(m, 2H) 3,52(m, 2H) 3,5(m, 1H) 3,42(s, 3H) 3,25(m, 1H) 2,7(m, 1H) 3,49(s, 3H) 3,41(s, 3H) 1,7(m, 1H) 1,60(m, 1H) 3,43(s, 3H) 3,40(m, 1H) 1,46(m, 1H) 1,25(m, 1H) 3,39(s, 3H) 3,08(m, 1H) 1,25(trtr, 6H) 1,2(trtr, 6H) 1,0(tr, 3H) 0,95(tr, 3H)

EXAMPLE 4.0 Production of the Free Aldehydes

148 mg (0.5 mmol) of intermediate product compound 1.18 is dissolved in 1 ml of glacial acetic acid. At room temperature, 0.5 ml of 1N hydrochloric acid is added, and it is stirred for 12 hours. For working-up, it is poured onto ice water and carefully neutralized with pulverized sodium bicarbonate. Then, it is extracted 3× with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. Crude product 104 mg (83% of theory) of the aldehyde of compound 4.0 is obtained. The crude product can be used without further purification.

Exam- ple No. 4.1 4.0 4.2 4.3 Yield 82% 83% 89% 79% Mass ESI: ESI: ESI: ESI: MH⁺ 278 MH⁺ 250 MH⁺ 266 MH⁺ 294 (39%) (9%) (8%) (10%) 210(100%)

EXAMPLE 5.0 Production of Ketones

100 mg (0.356 mmol) of compound 6.0 and 126 mg of N-methylmorpholine-N-oxide are dissolved in 5 ml of dichloromethane and stirred for 10 minutes with pulverized molecular sieve (4 A). Then, 6 mg of tetrapropylammonium perruthenate is added, and it is stirred for 4 more hours at room temperature. After concentration by evaporation, it is chromatographed on silica gel (hexane/ethyl acetate 4:1>2:1). Yield: 75 mg (76% of theory) of the ketone of compound 5.0.

Example No. 5.0 Yield 76% Mass ESI: MH⁺ 280 (100%) 200(37%) 156(30%)

EXAMPLE 6.0 Production of Alcohols

265 mg (1 mmol) of compound 4.2 is dissolved in 20 ml of tetrahydrofuran. While being cooled in an ice bath, 5 equivalents of methylmagnesium bromide (3 molar solution in ether) is added in portions. Then, it is stirred for 3 more hours at room temperature and then quenched with water while being cooled. Then, it is mixed with ammonium chloride solution, extracted 3× with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. Flash chromatography (hexane/ethyl acetate 2:1) yields 213 mg (76% of theory) of the alcohol of compound 6.0.

ESI:MH⁺ 282 (100%) 276 (5%)

Similarly produced are also the following intermediate products:

Exam- ple No. 6.1 6.2 6.3 Yield 46% 32% 39% Mass EI: ESI: ESI: M⁺ 267(3%) MH⁺ 308 MH⁺ 296 223(100%) (100%) (100%) 132(27%) 306(71%) 294(73%) 268(31%) 217(4%)

Exam- ple No. 6.4 6.5 Yield 36% 50% Mass EI ESI: M⁺ 281 MH⁺ 310 (3%) (100%) 223(100%) 308(87%) 114(38%) 298(9%)

Exam- ple No. 6.6 6.7 6.8 Yield 40% 20% 35% Mass EI: CI: ESI: M⁺ 358 M⁺ 310 (100%) MH⁺ 294 (100%) 308 (84%) (28%) 356(97%) 130(54%) 296(36%) 277(29%) 210(100%)

Exam- ple No. 6.9 6.10 Yield 29% 67% Mass ESI: ESI: MH⁺ 308 MH⁺ 310(87%) (28%) 312(100%) 310 123(24%) (38%) 210 (100%)

Subjects of this invention are thus also compounds of general formula Ia

in which

D stands for halogen, and X, R¹, and R² have the meanings that are indicated in general formula (I).

Those intermediate products of general formula Ia, in which D stands for chlorine and X, R¹ and R² have the meanings that are indicated in the general formula, are especially valuable.

Another subject of this invention are also those compounds that fall under industrial property right DE 4029650, whose action is in the fungicide range and which are not described as CDK inhibitors, however, and also their use for treating cancer is not described.

No. Structure Name  5

4-[[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]amino]-phenol  6

4-[[5-Bromo-4-(2-propynyloxy)-2-pyrimidinyl]amino]-phenol 16

5-Bromo-N2-(4-methylthiophenyl)-N4-2-propynyl-2,4-pyrimidine diamine 22

1-[4-[(5-Bromo-4-(2-propynyloxy)-2-pyrimidinyl)amino]phenyl]-ethanone 23

5-Bromo-N2-(4-difluoromethylthiophenyl)-N4-2-propynyl-2,4-pyrimidine diamine 24

5-Bromo-N4-2-propynyl-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidine diamine 35

5-Bromo-N4-2-propynyl-N2-(3-trifluoromethylthiophenyl)-2,4-pyrimidine diamine 37

N-[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]-indazol-5-amine 38

N-[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]-benzothiazole-5-amine 42

4-[[5-Fluoro-4-(2-propynyloxy)-2-pyrimidinyl]amino]-phenol 43

4-[[5-Chloro-4-(2-propynyloxy)-2-pyrimidinyl]amino]-phenol 50

1-[4-[(5-Bromo-4-(2-propynylamino)-2-pyrimidinyl)amino]phenyl]-ethanone 54

1-[4-[(5-Iodo-4-(2-propynylamino)-2-pyrimidinyl)amino]phenyl]-ethanone 70

1-[4-[(5-Ethyl-4-(2-propynylamino)-2-pyrimidinyl)amino]phenyl]-ethanone 81

1-[4-[(5-Bromo-4-(2-propynylamino)-2-pyrimidinyl)aminolphenyl]-ethanol 82

1-[4-[(5-Bromo-4-(2-propynyloxy)-2-pyrimidinyl)amino]phenyl]-ethanol

The invention thus relates in addition to pharmaceutical agents that comprise a compound of general formula I

in which

-   -   R¹ stands for halogen or C₁-C₃-alkyl     -   X stands for oxygen or —NH,     -   A stands for hydrogen     -   B stands for hydroxy, —CO-alkyl-R⁷, —S—CHF₂,         —S—(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —S—CF₃, or —CH—(OH)—CH₃, or     -   A and B, independently of one another, can form a group

R², R³, R⁴, R⁷ and R⁸ have the meanings that are indicated in general formula I, as well as isomers, diastereomers, enantiomers and salts thereof.

The agents according to the invention can also be used for treating cancer, auto-immune diseases, cardiovascular diseases, chemotherapy agent-induced alopecia and mucositis, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, whereby cancer is defined as solid tumors and leukemia; auto-immune diseases are defined as psoriasis, alopecia and multiple sclerosis; cardiovascular diseases are defined as stenoses, arterioscleroses and restenoses; infectious diseases are defined as diseases that are caused by unicellular parasites; nephrological diseases are defined as glomerulonephritis; chronic neurodegenerative diseases are defined as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases are defined as ischemias of the brain and neurotraumas; and viral infections are defined as cytomegalic infections, herpes, hepatitis B or C, and HIV diseases.

The following examples describe the biological action of the compounds according to the invention without limiting the invention to these examples.

EXAMPLE 1 CDK2/CycE Kinase Assay

Recombinant CDK2- and CycE-GST-fusion proteins, purified from baculovirus-infected insect cells (Sf9), are obtained by Dr. Dieter Marmé, Klinik für Tumorbiologie, [Clinic for Tumor Biology], Freiburg. Histone IIIS, which is used as a kinase substrate, is purchased by the Sigma Company.

CDK2/CycE (50 ng/measuring point) is incubated for 15 minutes at 22° C. in the presence of various concentrations of test substances (0 μm, as well as within the range of 0.01-100 μm) in assay buffer [50 mmol of tris/HCl pH 8.0, 10 mmol of MgCl₂, 0.1 mmol of Na ortho-vanadate, 1.0 mmol of dithiothreitol, 0.5 μm of adenosine triphosphate (ATP), 10 μg/measuring point of histone IIIS, 0.2 μCi/measuring point of ³³P-gamma ATP, 0.05% NP40, 12.5% dimethyl sulfoxide]. The reaction is stopped by adding EDTA solution (250 mmol, pH 8.0, 14 μl/measuring point).

From each reaction batch, 10 μl is applied to P30 filter strips (Wallac Company), and non-incorporated ³³P-ATP is removed by subjecting the filter strips to three washing cycles for 10 minutes each in 0.5% phosphoric acid. After the filter strips are dried for one hour at 70° C., the filter strips are covered with scintillator strips (MeltiLex™ A, Wallac Company) and baked for one hour at 90° C. The amount of incorporated ³³P (substrate phosphorylation) is determined by scintillation measurement in a gamma-radiation measuring device (Wallac).

EXAMPLE 2 Proliferation Assay

Cultivated human tumor cells (as indicated) are flattened out at a density of 5000 cells/measuring point in a 96-hole multititer plate in 200 μl of the corresponding growth medium. After 24 hours, the cells of one plate (zero-point plate) are colored with crystal violet (see below), while the medium of the other plates is replaced by fresh culture medium (200 μl), to which the test substances are added at various concentrations (0 μm, as well as in the range of 0.01-30 μm; the final concentration of the solvent dimethyl sulfoxide is 0.5%). The cells are incubated for 4 days in the presence of test substances. The cell proliferation was is determined by coloring the cells with crystal violet: the cells are fixed by adding 20 μl/measuring point of a 11% glutaric aldehyde solution for 15 minutes at room temperature. After three washing cycles of the fixed cells with water, the plates are dried at room temperature. The cells are colored by adding 100 μl/measuring point of a 0.1% crystal violet solution (pH was is set at 3 by adding acetic acid). After three washing cycles of the colored cells with water, the plates are dried at room temperature. The dye is dissolved by adding 100 μl/measuring point of a 10% acetic acid solution. The extinction is determined by photometry at a wavelength of 595 nm. The change of cell growth, in percent, is calculated by standardization of the measured values to the extinction values of the zero-point plate (=0%) and the extinction of the untreated (0 μm) cells (=100%).

The results of Examples 1 and 2 are cited in the following tables.

Inhibition Example IC₅₀ [nM] Proliferation IC₅₀ [μM] Sw Nummer CDK2/CycE MCF7 H460 HCT116 DU145 (g/l) 22 40 1.2 1.5 1.5 1.5 0.003 37 70 4 0.006 6 70 4 6 0.008 40 20 1 3 3 9 0.002 51 70 8 20 60 4 21 400 2 1 300 8 2 700 16 300 3 24 400 5 26 300 3 35 120 >10 23 180 3 11 6 0.2 0.5 0.3 0.2 38 80 >10 34 1800 10 4 0.2 0.5 0.5 0.5 12 400 4 25 70 1.2 1.5 1.1 1.2 0.017 9 7 0.9 3 3 7 6 0.7 1.5 1.2 0.5 0.028 31 800 7 0.0023 14 200 3 0.013 18 2000 0.039 3 200 8 0.039 19 800 >10 0.041 13 2000 >10 17 1000 >10 0.04 4 40 8 0.042 15 300 >10 0.024 8 <10 4 0.007 43 200 6 0.04 36 30 0.4 0.6 0.5 0.6 0.018 27 >10000 42 2000 0.043 39 300 0.0016 44 8 1.2 0.4 0.4 0.3 0.005 45 10 2 1.7 1.2 0.5 0.0094 50 150 5 90 10 0.043 46 7 2 0.0069 52 200 0.2 1.6 1.2 2 0.0005 53 300 1.6 0.026 54 100 1.1 0.0015 47 12 0.7 1.8 1.3 0.9 56 80 4 0.023 49 50 >10 0.044 48 4 0.2 1 0.4 0.3 0.042 96 400 0.0005 98 2000 85 2000 0.001 84 400 0.0005 86 3000 87 250 0.8 0.003 22 40 1.2 1.5 1.5 1.5 0.003 37 70 4 0.006 6 70 4 6 0.008 16 300 3 24 400 5 35 120 >10 23 180 3 38 80 >10 43 200 6 0.04 42 2000 0.043 50 150 5 90 10 0.043 54 100 1.1 0.0015

Proof of Superiority of the Compounds According to the Invention Compared to the Known Compounds

To prove the superiority of the compounds according to the invention compared to the known compounds, the compounds according to the invention are compared to known reference compounds and structurally-similar known compounds in the enzyme test. The result is cited in the following table:

CDK2/ Solubil- CycE MCF-7 ity Example No. R² A IC₅₀ [nM] IC₅₀ [μM] (g/l)

CH(C₃H₇—CH₂—OH— —SO₂—N—(CH₂)₂—OH 4 0.2 0.042 No. 48

CH(CH₂OH)₂ SO₂NH₂ 7 0.9 0.009 No. 9

Propargyl—NH— SO₂NH₂ 6 0.2 No. 11

7000 30 Olomoucine

1500 8 Roscovitine

1800 6 Kenpaullone

90 1.2 Alsterpaullone

10 2 Purvalanol A Example 11 from 190 WO01/14375 (page 38)

It can be seen from the results of the table that both in the enzyme test and in the cell test, the compounds according to the invention have significantly higher activities in the enzyme and in the MCF-7 cells than the compounds that are known from the prior art. The compounds according to the invention are thus far superior to the known compounds. 

1. A compound of formula I

wherein R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, or —(CH₂)_(n)R⁵, R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, or C₃-C₁₀-cycloalkyl, or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, or C₃-C₁₀-cycloalkyl each of which is substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)_(n)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, and —(CH₂)_(n)-aryl groups themselves optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, benzoxy or with the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and C₁-C₁₀ alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms or R² stands for the group

X stands for oxygen or for the group —NH—, or —N(C₁-C₃-alkyl)- or for —OC₃-C₁₀-cycloalkylene, or X and R² together form a C₃-C₁₀-cycloalkyl ring, which optionally can be substituted in one or more places with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, A independently stands for —SO₂R⁷, B independently of A stands for hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —SR⁷, —S(O)R⁷, —SO₂R⁷, —NHSO₂R⁷, —CH(OH)R⁷, —CR⁷(OH)—R⁷, C₁-C₆-alkylP(O)OR³OR⁴ or —COR⁷, R³ and R⁴, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy, C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with cyano, or for C₁-C₆-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy, wherein the phenyl itself can be substituted in one or more places in the same way or differently with halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴, or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴, or R³ and R⁴ together form a C₃-C₁₀-cycloalkyl ring that optionally can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy, R⁶ stands for a C₃-C₁₀-cycloalkyl ring, that optionally can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₁₀-cycloalkyl, with the above-indicated meaning, or for the group —NR³R⁴, or for a C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl or C₃-C₇-cycloalkyl that is substituted in one or more places in the same way or differently with hydroxy, C₁-C₆-alkoxy, halogen, phenyl, —NR³R⁴ or phenyl, which itself can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, or R⁷ stands for phenyl, which itself can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl or C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, or halo-C₁-C₆-alkoxy, R⁸, R⁹ and R¹⁰, in each case independently of one another, stand for hydrogen, hydroxy, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, C₃-C₁₀-cycloalkyl, aryl, or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)_(n)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, and —(CH₂)_(n)-aryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃ or —OCF₃, and the ring of C₃-C₁₀-cycloalkyl can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and C₁-C₁₀ alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and n stands for 0-6, or a pharmaceutically acceptable salt thereof.
 2. A compound according to claim 1, wherein R⁷ is a C₁-C₆-alkyl or a C₁-C₁₀-alkyl substituted in one or more places in the same way or differently with hydroxy, C₁-C₆-alkoxy, halogen, —NR³R⁴ or phenyl.
 3. A compound according to claim 1, wherein X is —NH—.
 4. A compound according to claim 2, wherein X is —NH—.
 5. A compound according to claim 1, wherein R¹ is halogen.
 6. A compound according to claim 2, wherein R¹ is halogen.
 7. A compound according to claim 3, wherein R¹ is halogen.
 8. A compound according to claim 4, wherein R¹ is halogen.
 9. A compound according to claim 3, wherein R² is C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)_(n)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴.
 10. A compound according to claim 2, wherein R² is C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)_(n)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴.
 11. A compound according to claim 9, wherein R² is C₁-C₁₀-alkyl optionally substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴.
 12. A compound according to claim 9, wherein R² is C₁-C₁₀-alkyl substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴.
 13. A compound according to claim 9, wherein R² is C₁-C₁₀-alkyl substituted with hydroxy.
 14. A compound according to claim 10, wherein R² is C₁-C₁₀-alkyl optionally substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)_(n)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴.
 15. A compound according to claim 10, wherein R² is C₁-C₁₀-alkyl substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)_(n)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴.
 16. A compound according to claim 10, wherein R² is C₁-C₁₀-alkyl substituted with hydroxy.
 17. A compound according to claim 1, wherein one of A or B is —SO₂R⁷ and the other is hydrogen.
 18. A compound according to claim 1, wherein one of A or B is —SO₂R⁷ in a meta or para position.
 19. A compound according to claim 1, of the formula:

or a pharmaceutically acceptable salt thereof.
 20. A compound according to claim 1, of the formula:

or a pharmaceutically acceptable salt thereof.
 21. A compound according to claim 1, of the formula:

or a pharmaceutically acceptable salt thereof.
 22. A compound according to claim 1, of the formula:

or a pharmaceutically acceptable salt thereof.
 23. A compound according to claim 1, of the formula:

or a pharmaceutically acceptable salt thereof.
 24. A compound according to claim 1, of the formula:

or a pharmaceutically acceptable salt thereof.
 25. A compound according to claim 1, of the formula:

or a pharmaceutically acceptable salt thereof.
 26. A compound according to claim 1, of the formula:

or a pharmaceutically acceptable salt thereof.
 27. A compound according to claim 19, in the form of a diastereomer or an enantiomer.
 28. A compound according to claim 1, in the form of a diastereomer or an enantiomer.
 29. A compound according to claim 20, in the form of a diastereomer or an enantiomer.
 30. A compound according to claim 21, in the form of a diastereomer or an enantiomer.
 31. A compound according to claim 22, in the form of a diastereomer or an enantiomer.
 32. A compound according to claim 23, in the form of a diastereomer or an enantiomer.
 33. A compound according to claim 24, in the form of a diastereomer or an enantiomer.
 34. A compound according to claim 25, in the form of a diastereomer or an enantiomer.
 35. A compound according to claim 26, in the form of a diastereomer or an enantiomer.
 36. A compound according to claim 1, in the form of a diastereomer or an enantiomer.
 37. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier.
 38. A compound of claim 1 wherein R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, —C₂H₄OH, or —NR³R⁴, R⁸, R⁹ and R¹⁰, in each case independently of one another, stand for hydrogen, hydroxy, C₁-C₆-alkyl, C₃-C₆-cycloalkyl or for the group

and n stands for 0-6.
 39. A compound according to claim 1, wherein R¹ stands for hydrogen, halogen, C₁-C₃-alkyl, or for the group —(CH₂)_(n)R⁵, R² stands for —CH(CH₃)—(CH₂)_(n)—R⁵, —CH—(CH₂OH)₂, —(CH₂)_(n)R⁷, —CH(C₃H₇)—(CH₂)_(n)—R⁵, —CH(C₂H₅)—(CH₂)_(n)—R⁵, —CH₂—CN, —CH(CH₃)COCH₃, —CH(CH₃)—C(OH)(CH₃)₂, —CH(CH(OH)CH₃)OCH₃, —CH(C₂H₅)CO—R⁵, C₂-C₄-alkynyl, —(CH₂)_(n)—COR⁵, —(CH₂)_(n)—CO—C₁-C₆-alkyl, —(CH₂)_(n)—C(OH) (CH₃)-phenyl, —CH(CH₃)—C(CH₃)—R⁵, —CH(CH₃)—C(CH₃) (C₂H₅)—R⁵, —CH(OCH₃)—CH₂—R⁵, —CH₂CH(OH)—R⁵, —CH(OCH₃)—CHR⁵—CH₃, —CH(CH₃)—CH(OH)—CH₂—CH═CH₂, —CH (CH₂)_(n)—CH₃, —CH(CH₃)—CH(OH)—(CH₂)_(n)—CH₃, —CH(CH₃)—CH(OH)—CH(CH₃)₂, (CH₂OAc)₂, —(CH₂)_(n)—R⁶, —(CH₂)_(n)—(CF₂)_(n)—CF₃, —CH((CH₂)_(n)—R⁵)₂, —CH (CH₃)—CO—NH₂, —CH(CH₂OH)-phenyl, —CH(CH₂OH)—CH(OH)—(CH₂)_(n)R⁵, —CH(CH₂OH)—CH(OH)-phenyl, —CH (CH₂OH)—C₂H₄—R⁵, —(CH₂)_(n)—C≡C—C(CH₃)═CH—COR⁵, —CH(Ph)—(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂, —CH((CH₂)_(n)OR⁵)CO—R⁵, —(CH₂)_(n)CONHCH((CH₂)_(n)R⁵)₂, —(CH₂)_(n)NH—COR⁵, —CH(CH₂)_(n)R⁵—(CH₂)_(n)C₃-C₁₀-cycloalkyl, —(CH₂)_(n)—C₃-C₁₀-cycloalkyl or, C₃-C₁₀-cycloalkyl, C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl, —(CH₂)_(n)—O—(CH₂)_(n)—R⁵, or —(CH₂)_(n)—NR³R⁴, —CH(C₃H₇)—(CH₂)_(n)—OC (O)—(CH₂)_(n)CH₃, —(CH₂)_(n)—R⁵, —C (CH₃)₂—(CH₂)_(n)—R⁵, —C(CH₂)_(n)(CH₃)—(CH₂)_(n)R⁵,—C(CH₂)_(n)—(CH₂)_(n)R⁵, —CH (t-butyl)-(CH₂)_(n)—R⁵, —CCH₃(C₃H₇)—(CH₂)_(n)R⁵, —CH(C₃H₇)—(CH₂)_(n)—R⁵, —CH (C₃H₇)—COR⁵, —CH (C₃H₇)—(CH₂)_(n)—OC(O)—NH—Ph, —CH((CH₂)_(n)(C₃H₇))—(CH₂)_(n)R⁵—CH (C₃H₇)—(CH₂)_(n)—OC (O)—NH—Ph(OR⁵)₃, R⁵—(CH₂)_(n)—C*H—CH(R⁵)—(CH₂)_(n)—R⁵, -(CH₂)_(n)CO—NH—(CH₂)_(n)—CO—R⁵, or —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CH—((CH₂)_(n)R⁵)₂, each of which is optionally substituted in one or more places in the same way or differently with hydroxy, C₁-C₆-alkyl or the group —NR³R⁴, or for C₃-C₁₀-cycloalkyl, which is substituted with the group

or for the group

X stands for the group —NH—, or —N(C₁-C₃-alkyl) or R² stands for the group

B stands for hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —S—CH₃, —SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂, —S(CH₂)_(n)CH(OH) CH₂N—R³R⁴, —CH₂PO(OC₂H₅)₂, —S—CF₃, —SO—CH₃, —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴, —SO₂—NR³R⁴, —SO₂R⁷, —CH(OH)—CH₃, —COOH, —CH ((CH₂)_(n)R⁵)₂, —(CH₂)_(n)R⁵, —COO—C₁-C₆-alkyl, or —CONR³R⁴, R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, —(CH₂)_(n)OH, or —NR³R⁴ R⁸, R⁹ and R¹⁰ stand for hydrogen, hydroxy, C₁-C₆-alkyl or for the group —(CH₂)_(n)—COOH, and n stands for 1-6.
 40. A compound according to claim 1, wherein B is H and X is —NH—.
 41. A compound according to claim 1, wherein B is CH₃ and X is —NH—.
 42. A compound according to claim 1, wherein X is —NH—.
 43. A compound according to claim 42, wherein one of R³ and R⁴ is H or methyl and the other is hydrogen, hydroxy, methyl, butyl, hexyl, heptyl, octyl, nonyl, decyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxymethyl-2-hydroxyethyl, ethoxy, 2-methoxyethyl, prop-2-eneoxy, benzyloxy, 3-hydroxypropyl, 3-hydroxybutyl, 5-hydroxypentyl, cyclopropylmethyl, 4-cyanocyclohexylmethyl, cyclohexylmethyl, 2-methoxyphenylmethyl, 4-methylphenylmethyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl, 2-methoxyphenylmethyl, 3,4-dimethoxyphenylmethyl, 2-phenyloxyethyl, 3,3-diphenylpropyl, phenylmethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 2-phenoxyethyl, 4-chloro-2-phenylethyl, 4-methoxyphenylethyl, 3-methylbutyl, cyclopropyl, or 4-sulfoaminophenylethyl.
 44. A compound according to claim 43, wherein one of R³ and R⁴ is H or methyl and the other is hydrogen, methyl, hexyl, heptyl, octyl, nonyl, 2-hydroxyethyl, 2-methoxyethyl, 4-cyanocyclohexylmethyl, cyclohexylmethyl, 4-methylphenylmethyl, 2-methoxyphenylmethyl, 3,3-diphenylpropyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 4-chloro-2-phenylethyl, or 3-methylbutyl.
 45. A compound according to claim 44, wherein both R³ and R⁴ are hydrogen.
 46. A compound according to any one of claims 42, 43, 44 or 45 wherein B is H or methyl.
 47. A compound according to claim 46, wherein B is H.
 48. A compound according to any one of claims 42, 43, 44 or 45 wherein R¹ is fluorine, bromine, chlorine, iodine, hydrogen, methyl, or ethyl.
 49. A compound according to claim 46, wherein R¹ is fluorine, bromine, chlorine, iodine, hydrogen, methyl, or ethyl.
 50. A compound according to claim 47, wherein R¹ is fluorine, bromine, chlorine, iodine, hydrogen, methyl, or ethyl.
 51. A compound according to claim 48, wherein R¹ is bromine, chlorine, iodine, or methyl.
 52. A compound according to claim 49, wherein R¹ is bromine, chlorine, iodine, or methyl.
 53. A compound according to claim 50, wherein R¹ is bromine, chlorine, iodine, or methyl.
 54. A compound according to claim 51, wherein R¹ is bromine.
 55. A compound according to claim 52, wherein R¹ is bromine.
 56. A compound according to claim 53, wherein R¹ is bromine.
 57. A compound according to any one of claims 42, 43, 44 or 45, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 58. A compound according to claim 46, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 59. A compound according to claim 47, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 60. A compound according to claim 48, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 61. A compound according to claim 49, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 62. A compound according to claim 50, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 63. A compound according to claim 51, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 64. A compound according to claim 52, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 65. A compound according to claim 53, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 66. A compound according to claim 54, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 67. A compound according to claim 55, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 68. A compound according to claim 56, wherein R² is (2R)-1-hydroxy-3-methylbut-2-yl, 2-propynyl, 1-hydroxybut-2-yl, 2-hydroxybut-3-yl, 1-hydroxyprop-2-yl, or methyl prop-2-yl ether.
 69. A compound according to claim 57, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 70. A compound according to claim 58, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 71. A compound according to claim 59, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 72. A compound according to claim 60, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 73. A compound according to claim 61, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 74. A compound according to claim 62, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 75. A compound according to claim 63, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 76. A compound according to claim 64, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 77. A compound according to claim 65, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 78. A compound according to claim 66, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 79. A compound according to claim 67, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 80. A compound according to claim 68, wherein R² is 1-hydroxybut-2-yl or 1-hydroxyprop-2-yl.
 81. A compound according to claim 1, wherein one of R³ and R⁴ is H or methyl and the other is hydrogen, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy, C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with cyano, or C₁-C₆-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy, wherein the phenyl groups can be substituted in one or more places in the same way or differently with halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴.
 82. A compound according to claim 42, wherein one of R³ and R⁴ is H.
 83. A compound according to claim 43, wherein one of R³ and R⁴ is H.
 84. A composition comprising a compound of claim 46 and a pharmaceutically acceptable carrier.
 85. A composition comprising a compound of claim 48 and a pharmaceutically acceptable carrier.
 86. A composition comprising a compound of claim 57 and a pharmaceutically acceptable carrier.
 87. A compound of formula I

wherein R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, —COR⁵, —OCF₃, or —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃. R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, or C₃-C₁₀-cycloalkyl, or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, or C₃-C₁₀-cycloalkyl each of which is substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N (C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)_(n)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, and —(CH₂)_(n)-aryl groups themselves optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, benzoxy or with the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and C₁-C₁₀ alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms or R² stands for the group

X stands for oxygen or for the group —NH—, or —N(C₁-C₃-alkyl)- or for —OC₃-C₁₀-cycloalkylene, or X and R together form a C₃-C₁₀-cycloalkyl ring, which optionally can be substituted in one or more places with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, A independently stands for —SO₂R⁷, B independently of A stands for hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —SR⁷, —S(O)R⁷, —SO₂R⁷, —NHSO₂R⁷, —CH(OH)R⁷, —CR⁷(OH)—R⁷, C₁-C₆-alkylP(O)OR³OR⁴ or —COR⁷, R³ and R⁴, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy, C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with cyano, or for C₁-C₆-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy, wherein the phenyl itself can be substituted in one or more places in the same way or differently with halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴, or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴, or R³ and R⁴ together form a C₃-C₁₀-cycloalkyl ring that optionally can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy, R⁶ stands for a C₃-C₁₀-cycloalkyl ring, that optionally can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₁₀-cycloalkyl, with the above-indicated meaning, or for the group —NR³R⁴, or for a C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl or C₃-C₇-cycloalkyl that is substituted in one or more places in the same way or differently with hydroxy, C₁-C₆-alkoxy, halogen, phenyl, —NR³R⁴ or phenyl, which itself can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, or R⁷ stands for phenyl, which itself can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl or C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, or halo-C₁-C₆-alkoxy, R⁸, R⁹ and R¹⁰, in each case independently of one another, stand for hydrogen, hydroxy, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, C₃-C₁₀-cycloalkyl, aryl, or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)_(n)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, and —(CH₂)_(n)-aryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃ or —OCF₃, and the ring of C₃-C₁₀-cycloalkyl sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and C₁-C₁₀ alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and n stands for 0-6, or a pharmaceutically acceptable salt thereof.
 88. A compound of formula I

wherein R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, nitro, —COR⁵, —OCF₃, or —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃, R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, or C₃-C₁₀-cycloalkyl, or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, or C₃-C₁₀-cycloalkyl each of which is substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)_(n)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, and —(CH₂)_(n)-aryl groups themselves optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, benzoxy or with the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and C₁-C₁₀ alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms or R² stands for the group

X stands for oxygen or for the group —NH—, or —N(C₁-C₃-alkyl)- or for —OC₃-C₁₀-cycloalkylene, or X and R together form a C₃-C₁₀-cycloalkyl ring, which optionally can be substituted in one or more places with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, A independently stands for —SO₂R⁷, B independently of A stands for hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —SR⁷, —S(O)R⁷, —SO₂R⁷, —NHSO₂R⁷, —CH(OH)R⁷, —CR⁷(OH)—R⁷, C₁-C₆-alkylP(O)OR³OR⁴ or —COR⁷, R³ and R⁴, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy, C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with cyano, or for C₁-C₆-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy, wherein the phenyl itself can be substituted in one or more places in the same way or differently with halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴, or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴, or R³ and R⁴ together form a C₃-C₁₀-cycloalkyl ring that optionally can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy, R⁶ stands for a C₃-C₁₀-cycloalkyl ring, that optionally can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₁₀-cycloalkyl, with the above-indicated meaning, or for the group —NR³R⁴, or for a C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl or C₃-C₇-cycloalkyl that is substituted in one or more places in the same way or differently with hydroxy, C₁-C₆-alkoxy, halogen, phenyl, —NR³R⁴ or phenyl, which itself can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, or R⁷ stands for phenyl, which itself can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl or C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, or halo-C₁-C₆-alkoxy, R⁸, R⁹ and R¹⁰, in each case independently of one another, stand for hydrogen, hydroxy, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, C₃-C₁₀-cycloalkyl, aryl, or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places in the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl, —(CH₂)_(n)-aryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, and —(CH₂)_(n)-aryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃ or —OCF₃, and the ring of C₃-C₁₀-cycloalkyl sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and C₁-C₁₀ alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and n stands for 0-6, or a pharmaceutically acceptable salt thereof, with the proviso that said compound is not 2-(4-aminosulfonyl-phenylamino)-4-methylamino-5-nitro-pyrimidine and is not 2-(4-methylsulfonylphenylamino)-4-methylamino-5-nitropyrimidine.
 89. A compound according to claim 1, wherein R¹ stands for hydrogen, halogen, C₁-C₃-alkyl, or for the group —(CH₂)_(n)R⁵, R² stands for —CH(CH₃)—(CH₂)_(n)—R⁵, —CH—(CH₂OH)₂, —(CH₂)_(m)R⁷, —CH(C₃H₇)—(CH₂)_(n)—R⁵, —CH(C₂H₅)—(CH₂)_(n)—R⁵, —CH₂—CN, —CH(CH₃) COCH₃, —CH(CH₃)—C(OH)(CH₃)₂, —CH(CH(OH)CH₃)OCH₃, —CH(C₂H₅)CO—R⁵, C₂-C₄-alkynyl, —(CH₂)_(m)—COR⁵, —(CH₂)_(m)—CO—C₁-C₆-alkyl, —(CH₂)_(n)—C(OH) (CH₃)-phenyl, —CH(CH₃)—C(CH₃)—R⁵, —CH(CH₃)—C(CH₃)(C₂H₅)—R⁵, —CH(OCH₃)—CH₂—R⁵, —CH₂—CH(OH)—R⁵, —CH(OCH₃)—CHR⁵—CH₃, —CH(CH₃)—CH(OH)—CH₂—CH═CH₂, —CH(C₂H₅)—CH(OH)—(CH₂)_(n)—CH₃, —CH(CH₃)—CH(OH)—(CH₂)_(n)CH₃, —CH(CH₃)—CH(OH)—CH(CH₃)₂, (CH₂OAc)₂, —(CH₂)_(n)—R⁶, —(CH₂)_(n)—(CF₂)_(n)—CF₃, —CH((CH₂)_(n)—R⁵)₂, —CH(CH₃)—CO—NH₂, —CH(CH₂OH)-phenyl, —CH(CH₂OH)—CH(OH)—(CH₂)_(n)R⁵, —CH(CH₂OH)—CH(OH)-phenyl, —CH(CH₂OH)—C₂H₄—R⁵, —(CH₂)_(n)—C≡C—C(CH₃)═CH—COR⁵, —CH(Ph)—(CH₂)_(n)—R⁵, —(CH₂)_(m)PO₃(R⁵)₂, —CH((CH₂)_(n)OR⁵)CO—R⁵, —(CH₂)_(m)CONHCH ((CH₂)_(n)R⁵)₂, —(CH₂)_(m)NH—COR⁵, —CH(CH₂)_(n)R⁵—(CH₂)_(n)C₃-C₁₀-cycloalkyl, —(CH₂)_(n)—C₃-C₁₀-cycloalkyl or, C₃-C₁₀-cycloalkyl, C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl, —(CH₂)_(m)—O—(CH₂)_(n)—R⁵, or —(CH₂)_(m)—NR³R⁴, —CH(C₃H₇)—(CH₂)_(n)—OC (O)—(CH₂)_(n)CH₃, —(CH₂)_(m)—R⁵, —C (CH₃)₂—(CH₂)_(n)—R⁵, —C (CH₂)_(n)(CH₃)—(CH₂)_(n)R⁵, —C (CH₂)_(n)—(CH₂)_(n)R⁵, —CH (t-butyl)-(CH₂)_(n)—R⁵, —CCH₃(C₃H₇)—(CH₂)_(n)R⁵, —CH (C₃H₇)—(CH₂)_(n)—R⁵. —CH (C₃H₇)—COR⁵, —CH(C₃H₇)—(CH₂)_(n)—OC (O)—NH—Ph, —CH ((CH₂)_(n)(C₃H₇))—(CH₂)_(n)R⁵, —CH (C₃H₇)—(CH₂)_(n)—OC (O)—NH—Ph(OR⁵)₃, R⁵—(CH₂)_(n)—C*H—CH (R⁵)—(CH₂)_(n)—R⁵, —(CH₂)_(m)—CO—NH—(CH₂)_(n)—CO—R⁵, or —(CH₂)_(m)—CO—NH—(CH₂)_(n)CH—((CH₂)_(n)R⁵)₂, each of which is optionally substituted in one or more places in the same way or differently with hydroxy, C₁-C₆-alkyl or the group —NR³R⁴, or for C₃-C₁₀-cycloalkyl, which is substituted with the group

or for the group

X stands for the group —NH—, or —N(C₁-C₃-alkyl) or R² stands for the group

B stands for hydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —S—CH₃, —SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂, —S (CH₂)_(n)CH(OH)CH₂N—R³R⁴, —CH₂PO(OC₂H₅)₂, —S—CF₃, —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴, —SO₂—NR³R⁴, —SO₂R⁷, —CH (OH)—CH₃, —COOH, —CH ((CH₂)_(n)R⁵)₂, —(CH₂)_(n)R⁵, —COO—C₁-C₆-alkyl, or —CONR³R⁴, R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, —(CH₂)_(n)OH, or —NR³R⁴ R⁸, R⁹ and R¹⁰ stand for halogen, hydroxy, C₁-C₆-alkyl or for the group —(CH₂)_(n)—COOH, n stands for 0-6, and m stands for 1-6.
 90. A compound according to claim 1, wherein B is H, OH, or CH₃; and X is —NH— or —N(C₁-C₃-alkyl). 